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The role of cancer-derived microRNAs in cancer immune escape


During malignant transformation, accumulated somatic mutations endow cancer cells with increased invasiveness and immunogenicity. Under selective pressure, these highly immunogenic cancer cells develop multiple strategies to evade immune attack. It has been well established that cancer cells could downregulate the expression of major histocompatibility complex, acquire alterations in interferon pathway, and upregulate the activities of immune checkpoint pathways. Besides, cancer cells secret numerous cytokines, exosomes, and microvesicles to regulate the functions and abundances of components in the tumor microenvironment including immune effector cells and professional antigen presentation cells. As the vital determinant of post-transcriptional regulation, microRNAs (miRNAs) not only participate in cancer initiation and progression but also regulate anti-cancer immune response. For instance, some miRNAs affect cancer immune surveillance and immune escape by interfering the expression of immune attack-associated molecules. A growing body of evidence indicated that cancer-derived immune modulatory miRNAs might be promising targets to counteract cancer immune escape. In this review, we summarized the role of some miRNAs in cancer immune escape and discussed their potential clinical application as treatment targets.


Robust anti-cancer immune response consists of a series of stepwise immune events including the release of cancer-associated antigens, the processing and presentation of antigen presentation cells (APCs), the priming and activation of naïve T cells, the trafficking and migration of activated T cells, and the tumor-killing activity of effector cells [1, 2]. Actually, the anti-cancer immune response is a highly complex process which could be strengthened or weakened by multiple factors such as immune editing, transforming growth factor-β (TGF-β) signaling, and immune checkpoints [3,4,5]. The balance between immuno-stimulatory and -inhibitory factors is crucial to maintain the immune homeostasis of host and clear the cancer-derived materials [6]. However, some immunosuppressive factors could be hijacked by cancer cells to evade immune attack. With the advancement of cancer immunology, it has been realized that these immune rheostats might be ideal targets for cancer immunotherapy [7]. In the last decade, the application of immune checkpoint inhibitors greatly propelled the development of cancer therapeutics [8,9,10]. Blocking immune checkpoint-associated pathways effectively reactivates exhausted effector cells to eliminate cancer cells.

For some patients, the undermined cytotoxicity of effector cells is not the only rate-limiting step of eliminating cancer cells. In these patients, alterations in some upstream events in cancer-immunity cycle such as the recognition of cancer antigens, the functions of APCs, and the infiltration of T cells hamper cancer immune clearance as well [11, 12]. Additionally, more and more studies demonstrated that cancer-derived microRNAs (miRNAs) are closely implicated in the formation of the immunosuppressive tumor microenvironment, disabled effector cells, as well as downregulated cancer immunogenicity [13, 14].

miRNAs are a class of small, non-coding, single-strand RNAs which could silence target mRNAs by binding to corresponding 3′-untranslated region (3′-UTR) or open reading frame [15]. It is well documented that miRNAs participate in various physiological and pathological processes including immune defense, immune surveillance, immune homeostasis, as well as carcinogenesis [16,17,18,19,20]. Some specific miRNA patterns are highly correlated with cancer initiation, progression, and drug resistance [21, 22]. Notably, miRNAs could mediate the intercellular communication through being packed into exosomes or microvesicles [23]. As the vital post-transcriptional regulators, some immune modulatory miRNAs affect the expression of a broad range of immunity-associated genes in both cancer cells and tumor infiltrating lymphocytes (TILs) [24].

Cancer immune escape

Although most patients have an intact immune system, some malignant cells could survive from immune attack and develop into clinically overt cancers [5]. Under the selective pressure of immune surveillance, cancer cells with high immunogenicity are preferentially eliminated by effector cells [25]. Eventually, cancer cells with weak immunogenicity escape immune clearance and become the predominant subpopulations [26]. The loss of immunoediting-mediated immunogenicity is a vital factor for cancer immune evasion. Moreover, other approaches could be utilized by cancer cells to produce immune evasion, such as inducing regulatory immune cells, acquiring disable antigen presentation machinery, upregulating immune checkpoints, and generating immunosuppressive microenvironment (Fig. 1) [27].

Fig. 1

The mechanisms by which cancer cells escape from immune attack of immune effector cells. Firstly, tumor-derived cytokines especially TGF-β remarkably reshape the tumor immune microenvironment. This immunosuppressive cytokine repertoire inhibits the functions of multiple effector cells, induces the differentiation of regulatory cells, and impedes the infiltration of T cells. Secondly, overexpressed immune checkpoints or their ligands such as PD-L1 on cancer cells promote the formation of exhausted TILs. Thirdly, cancer cells tend to harbor alterations in antigen processing machinery, which result in the loss of tumor-associated antigens and neoantigens. Mutations in major histocompatibility complex class I (MHC-I), proteasome subunits latent membrane protein, as well as transporter associated with antigen processing reduce the presentation of recognizable targets on cancer cells. Fourthly, overexpressed HLA-G on cancer cells binds to the inhibitory receptors on effector cells such as CTLs and NKs, leading to the suppression of the cytotoxic activities of these effector cells. Lastly, cancer cells could escape immune attack by downregulating NKG2D ligands including MICA, MICB, and UL16-binding protein. TAP transporter associated with antigen processing, MHC-I major histocompatibility complex class I, MICA/B MHC-I chain-related molecules A/B, IDO indoleamine 2, 3-dioxygenase, ULBP UL16-binding protein

Regulatory immune cells

Regulatory T cell (Treg) is an immunosuppressive class of CD4+ T cells [28]. In the tumor microenvironment, hyperactive Tregs could inhibit the tumor-killing activity of effector cells by secreting cytokines such as interleukin-10 (IL-10) and TGF-β [29]. Besides, Tregs promote cancer immune evasion by consuming IL-2 and upregulating the expression of multiple immune checkpoints including PD-L1, CTLA-4, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), V-domain Ig suppressor of T cell activation (VISTA), as well as T-cell immunoreceptor with Ig and ITIM domains (TIGIT) [30,31,32,33]. It has been recognized that Tregs plays an indispensable role in ICI resistance at the present stage [34]. Similarly to Tregs, a subset of B cells are identified as immune inhibitory cells which are termed Bregs [35]. Bregs could inhibit inflammation response by increasing the generation of PD-L1 and cytokines such as IL-10 [36, 37].

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous class of myeloid cell precursors which are halted at different stages of differentiation [38]. Abundant MDSCs in tumors induce cell cycle arrest of T cells via upregulating inducible nitric oxide synthase (iNOS) and arginase-1 (Arg1) [39]. Besides, MDSCs participate in oxidative stress and generate peroxynitrite which eventually blocks T cell activation [40]. Some MDSCs-derived materials such as IL-10, Arg1, and TGF-β could modulate the ratio of regulatory immune cells and effector cells [39]. Moreover, a specific phenotype of tumor-associated macrophages (TAMs), M2-type macrophages undermine anti-cancer immune response and promote immune evasion by anti-inflammation cytokines and immune checkpoint-associated pathways [41].

Disable antigen processing and presentation of cancer cells

The cytotoxicity of cancer-specific effector cells is highly dependent on antigens expressed on cancer cells. Cancer cells tend to harbor alterations in antigen processing machinery (APM), which result in the loss of tumor-associated antigens (TAAs) and neoantigens [5]. Mutations in major histocompatibility complex class I (MHC-I), proteasome subunits latent membrane protein (LMP), as well as transporter associated with antigen processing (TAP) reduce the presentation of recognizable targets on cancer cells [42]. As a result, cancer cells exhibiting low immunogenicity are prone to survive from immune attack.

Immune inhibitory cytokines and immune checkpoints

Tumor-derived cytokines especially TGF-β remarkably reshape the tumor immune microenvironment. This immunosuppressive cytokine repertoire inhibits the functions of multiple effector cells, induces the differentiation of regulatory cells, and impedes the infiltration of T cells [43, 44]. In addition, overexpressed immune checkpoints or their ligands such as PD-L1 on cancer cells promote the formation of exhausted TILs [45]. Moreover, some cancer cell-derived metabolites including indoleamine 2, 3-dioxygenase (IDO), arginase, and inhibitor of nuclear factor kappa-B kinase are greatly related to immune resistance in tumor as well [46,47,48].

The role of miRNAs in cancer immune evasion

Apart from acting as tumor promoters or suppressors, it has been revealed that a growing body of miRNAs could regulate cancer immune surveillance and escape [49]. A panel of miRNAs protect cancer cells from immune clearance by decreasing the immunogenicity of cancer cells and downregulating the magnitude of anti-cancer immune response (Fig. 2). Simultaneously, another group of miRNAs strengthen anti-cancer immune clearance. These immune modulatory miRNAs are termed im-miRNAs [50]. Cancer cell-derived im-miRNAs not only target themselves but also broadly regulate various immune components including MDSCs, Tregs, DCs, NKs, as well as cytotoxic T lymphocytes (CTLs) via intercellular communication (e.g., exosomes and microvesicles) [24, 51, 52].

Fig. 2

Cancer-derived miRNAs regulate immune evasion via modulating the expression profiles within cancer cells. Firstly, some immune modulatory miRNAs disturb antigen processing and presentation by targeting one or multiple components of APM (e.g., TAP1, LMP8, LMP9, and LMP10) and MHC-I molecules in cancer cells. Secondly, the loss of some HLA-G-targeting miRNAs is highly related with increased HLA-G expression, which is a well-accepted immune tolerant moelcule. Thirdly, cancer cells could escape immune attack by downregulating NKG2D ligands (MICA/B and ULBP2) in post-transcriptional level. Increased MICA/B- or ULBP2-targeting miRNAs protect cancer cells from immune clearence of NKs and CTLs. Fourthly, altered miRNA expressio pattern upregulates PD-L1 level in cancer cells. Lastly, dysregulated miRNA profiles change the metabolism of cancer cells. Increased IDO1 further hampered the normal immune survelliance. The miRNAs promoting anti-cancer immune response are exihibited in boxes with green background while the miRNAs inhbiting anti-cancer immune reponse are showed in boxes with red background. Upregualted immunostiumlatory miRNAs together with downregualted immunosuppressive miRNAs contribute to cancer immune evasion. APM antigen processing machinery, TAP transporter associated with antigen processing, MHC-I major histocompatibility complex class I, LMP proteasome subunits latent membrane protein, MICA/B MHC-I chain-related molecules A/B, ULBP UL16-binding protein, CTL cytotoxic T lymphocyte, IDO indoleamine 2, 3-dioxygenase

The miRNAs regulating cancer antigen processing and presentation

Some im-miRNAs disturb antigen processing and presentation by targeting one or multiple components of APM and MHC-I molecules in cancer cells (Table 1). Specifically speaking, in nasopharyngeal cancer cells, the results of microarray profiles indicated that miR-9 could target several APM components including TAP1, LMP8 (also termed PSMB8), LMP9 (PSMB9), LMP10 (PSMB10), and β2-microglobulin [53]. Besides, miR-9 significantly downregulates MHC-I molecules including human leukocyte antigen-B (HLA-B), HLA-C, HLA-F, and HLA-H [53]. The overexpression of miR-9 in multiple cancers such as cervical cancer, non-small cell lung cancer (NSCLC), and glioma might contribute to enhanced immune tolerance in the tumor microenvironment [57,58,59]. Meanwhile, some endoplasmic reticulum stress-associated miRNAs such as miR-346 regulates immune response by directly targeting TAP1 or indirectly suppressing the expression of MHC-I molecules and interferon (IFN) signaling pathway [60].

Table 1 The miRNAs regulating cancer antigen processing and presentation

Similarly, in esophageal adenocarcinoma cells, it has been verified that miR-125a-5p could bind to the 3′-UTR of TAP2 mRNA [54]. Also, it was detected that the 3′-UTR of HLA-A, HLA-B, and HLA-C mRNAs had the binding site for miR-148a-3p [54]. Meantime, the results of proteomic screening suggested that miR-27a promoted cancer progression by decreasing MHC-I expression on cell surface, inhibiting T cell infiltration and cytotoxic activities [56]. This miR-27a-induced MHC-I downregulation was dependent on calreticulin suppression [56].

HLA-G-targeting miRNAs

As a non-classic MHC-I molecule, HLA-G was initially found to maintain fetal-maternal tolerance [61]. This immune inhibitory function of HLA-G could be hijacked by cancer cells to escape immune attack [62]. Overexpressed HLA-G on cancer cells binds to the inhibitory receptors on effector cells such as CTLs and NKs, leading to the suppression of the cytotoxic activities of these effector cells [62]. Actually, it has been found that HLA-G expression was aberrantly elevated in multiple cancers including melanoma, breast cancer, colorectal cancer, lung cancer, gastric cancer, hepatocellular carcinoma, and endometrial carcinoma [63, 64].

In cancer cells, the increased HLA-G expression is closely correlated with the loss of some HLA-G-targeting miRNAs. Specifically, several members of miR-148 family such as miR-148a, miR-148b, and miR-152 could downregulate HLA-G expression [65,66,67]. In breast cancer cells, it was observed that oncogenic estrogenic G-protein-coupled estrogen receptor-1 (GPER) signaling pathway decreased downstream miR-148a level, further contributing to cancer immune evasion [68]. Additionally, miR-133a was verified as a vital mediator in maintaining peripheral immune tolerance by targeting HLA-G [69].

The MHC-I chain-related molecules A/B and miRNAs

The oncogenically transformed cells are susceptible to expressing a series of stress-induced ligands including MICA, MICB, and UL16-binding protein (ULBP) [70,71,72]. These ligands could be recognized by NKG2D on NKs and CTLs [70]. Intact NKG2D axis is an important signaling pathway to maintain cancer immune surveillance [73]. However, cancer cells could escape immune attack by downregulating NKG2D ligands in post-transcriptional level. So far, numerous miRNAs are portrayed as the modulators of NKG2D ligands (Table 2).

Table 2 The miRNA regulating NKG2D ligands

Previous studies demonstrated that overexpressed miR-20a in colorectal cancer cells, breast cancer cells, and ovarian cancer cells decreases MICA level and sensitivity to immune effector cells [74, 77,78,79]. Besides, it was found that miR-519a-3p undermined the tumor-killing effect of NKs by decreasing MICA and ULBP2 on breast cancer cells [81]. In breast cancer patients, high miR-519a-3p expression could be deemed as a predictive biomarker for poor prognosis [81]. In addition, Abruzzese et al. noticed that bromodomain and extra-terminal (BET) inhibitor could remarkably increase MICA expression on multiple myeloma cells [82]. This BETi-induced MICA elevation was mediated by miR-125b, which targeted the transcription suppressor of MICA (IRF4) [82]. Moreover, Kishikawa et al. found that miR-93 and miR-106b targeted the 3′-UTR of MICA mRNA [80]. Genes coding miR-93 and miR-106b are both located in human chromosome 7q22.1 (termed miR25-93-106b cluster) [80]. Silencing miR25-93-106b cluster significantly increased MICA expression and decreased the susceptibility of hepatocellular carcinoma cells to NKs [80]. Similarly to the observations of Kishikawa et al., Wu et al. noticed that a panel of miRNAs downregulated MHC-I chain-related molecules A/B (MICA/B) in hepatocellular carcinoma cells including miR-373, miR-29b, miR-15b, miR-195, miR-16, miR-424, miR-29c, miR-106a, miR-107, miR-20a, miR-29a, as well as miR-17 [75]. Notably, 1, 25-(OH)2-D3 treatment could promote cancer immune surveillance by counteracting miR-302c/miR-520c-induced downregulation of MICA/B and ULBP2 downregulation [83].

On the contrary to MICA expressed on cancer cells (also known as membrane MICA), soluble MICA (sMICA) is an unfavorable factor for anti-cancer immunity [84]. In pancreatic cancer cells, hypoxia-associated pathways conspicuously downregulated membrane MICA while simultaneously increased sMICA expression [84]. This hypoxia-induced sMICA upregulation was attributed to the dysregulated balance between circ_0000977 and miR-153 [84].

Immune checkpoint ligand-associated miRNAs

As a hallmark of cancer, upregulated immune checkpoint signal is determined by multiple factors, including previously existing inflammation and some oncogenic signaling pathways [85]. Increased immune checkpoint ligands especially PD-L1 is closely related with cancer-associated miRNA expression pattern. To be more specific, previous studies have indicated that the loss of miR-3609, miR-195-5p, miR-148a-3p, miR-873, miRNA-497-5p, miR-191-5p, miR-34a, and miR-138 closely correlated with the increased PD-L1 expression on numerous cancer cells [86,87,88,89,90,91,92,93,94]. In addition, Dong et al. found that decreased miR-140, miR-142, miR-340, and miR-383 enormously elevated PD-L1 expression on cervical cancer cells [95]. The results of a respective study demonstrated that in malignant pleural mesothelioma samples, the abundance of PD-L1 was negatively correlated with the levels of multiple cancer suppressive miRNAs including miR-15b, miR-16, miR-193a-3p, miR-195, and miR-200c [96]. Further investigation in cancer cell lines identified that miR-15b, miR-16, and miR-193a-3p could target PD-L1 mRNA [96]. Notably, some other long noncoding RNAs involved in the reduction of these PD-L1-targeting miRNAs [87, 94].

Contrarily, miR-18a promotes PD-L1 expression by targeting PTEN, WNK2, and SOX6 [95]. Then, PI3K-AKT, MEK-ERK, and Wnt/β-catenin pathways are activated and the transcription activity of PD-L1 is upregulated [95]. Similarly, Tang et al. observed miR-3127-5p induced PD-L1 expression by promoting STAT3 phosphorylation in NSCLC cells [97]. The miRNAs associated with PD-L1 expression on cancer cells were summarized in Table 3.

Table 3 The miRNAs regulating PD-L1 expression on cancer cells

The miRNAs and tumor-mediated immune cell death

Fas-FasL pathway has a great impact on immune tolerance in the tumor microenvironment [113]. Increased FasL on cancer cells counterattacks immune cells, induces immune cell death, and eventually promotes cancer immune privilege [114]. In T cell large granular lymphocyte leukemia, it was found that STAT3-induced miR-146b loss led to increased FasL expression and potential neutropenia [115]. Besides, the miR-768-3p mimic treatment in NSCLC cell immensely increased FasL level but decreased Fas expression on cancer cells [116]. Moreover, Wu et al. verified that miR-21 could target FasL in breast cancer cells. In the co-culture experiment, ectopically expressed miR-21 in MCF7 cells could remarkably reduce the apoptosis rate of Jurkat T cells [117]. Actually, FasL has been accepted as the post-transcriptional regulatory target of miR-21 in numerous cancer cell types including esophageal carcinoma and pancreatic cancer [118,119,120]. Notably, in spite of inhibiting immune evasion, highly expressed miR-21 was connected with cancer development, treatment resistance, and poor prognosis [118, 119].

Cancer cell metabolite-related miRNAs

Some cell metabolites such as tryptophan are essential to maintain the functions of TILs. IDO1 is a rate-limiting enzyme for tryptophan metabolism, which could convert tryptophan to kynurenine and 3-hydroxyanthranilic acid [121]. Increased IDO1 expression and decreased tryptophan lead to dysfunctional effector T cells and cancer immune evasion [122]. It was reported that downregulated miR-218 protected cervical cancer cells from immune attack via elevating IDO1 level [123]. Besides, Lou et al. found that miR-448 acted as a tumor suppressive factor by targeting downstream IDO1 in colon cancer cells. The results of in vitro study showed that the ectopic expression of miR-448 was beneficial to giving full play to the functions of TILs [124]. Moreover, Huang et al. reported that miR-153 level was a core factor determining the efficacy of chimeric antigen receptor (CAR) T cells treatment in colon cancer models. In colon cancer, miR-153 directly targeted IDO1, enhancing cytotoxic activity of CAR T cells and inhibiting tumor growth [46].

Cancer cell-derived miRNAs regulating immune evasion via exosomes or vehicles

Cancer-derived miRNAs not only modulate the expression profile within cancer cells but also exhibit extracellular bioactivities by exosomes or microvesicles (Table 4) [24]. Cancer-derived miRNAs could be packed into exosomes or microvesicles, which are transferred to numerous TILs and shape an immunosuppressive microenvironment (Fig. 3) [141].

Table 4 Cancer cells-derived miRNAs regulating immune evasion via exosomes or vehicles
Fig. 3

Cancer cells-derived miRNAs regulating immune evasion via exosomes or vehicles. Cancer-derived miRNAs could be packed into exosomes or microvesicles, which are transferred to numerous TILs and shape an immunosuppressive microenvironment. Cancer-derived exosomal miRNAs impair the cytotoxicity of effector cells, inducing the polarization of macrophages toward M2-like phenotype, promoting the expansion and the immunosuppressive activity of MDSCs, as well as inhibiting infiltration of lymphocytes via CAF-mediated matrix remodeling. TIL tumor-infiltrating lymphocyte, MDSC myeloid-derived suppressor cell, CAF cancer-associated fibroblast, TAM tumor-associated macrophage

Cancer-derived exosomal miRNAs and effector cells

Zhou et al. reported that the apoptosis ratio of T cells increased after treated with B16 cell-derived exosomes [125]. When the release of exosome was inhibited, the abundance of TILs elevated and tumor growth was retarded [125]. Further investigation found that the cancer-derived exosomes extraordinarily increased pro-apoptotic proteins (e.g., caspase-3/7/9) and decreased anti-apoptotic proteins (e.g., BCL-2/xL and MCL-1) in CD4+ T cells [125]. In silico analysis indicated that a group of cancer-derived exosomal miRNAs such as miR-690 might contribute to this mitochondrial apoptosis of T cells [125]. Besides, Ye et al. found that TW03 (nasopharyngeal carcinoma cell)-derived exosomes impaired the proliferation and differentiation of T cells [126]. Meanwhile, TW03-derived exosomes remarkably downregulated the generation of cytokines including IL-2, IFN-γ, and IL-17 [126]. It was proposed that a set of commonly overexpressed miRNAs (miR-24-3p, miR-891a, miR-106a-5p, miR-20a-5p, and miR-1908) were responsible for the undermined functions of T cells [126].

Cancer-derived exosomal miRNAs and TAMs

Macrophages are usually categorized into pro-inflammatory (M1) populations and anti-inflammatory (M2) populations [142]. Abundant M2-like TAMs in the tumor microenvironment promote carcinogenesis by inducing angiogenesis, suppressing anti-cancer immune response, and antagonizing cancer cell apoptosis [143]. Epithelial ovarian cancer cells induced the polarization of TMAs toward M2-like phenotype via secreting exosomal miR-222-3p and miR-940 [127, 128]. Besides, under hypoxic condition, epithelial ovarian cancer cell-secreted exosomes contained miRNAs such as miR-21-3p, miR-125b-5p, and miR-181d-5p, which enhanced the polarization of M2-like TAMs and promoted cancer growth [129]. Moreover, Hsieh et al. found that some snail-overexpressed cancer cells generated miR-21-containing exosomes during epithelial-mesenchymal transition (EMT) [130]. These exosomes were engulfed by CD14+ monocytes, inducing the polarization toward M2-like phenotype and suppressing the expression of M1 phenotype-associated markers [130]. Similarly, Cooks et al. observed that cancer cells harboring TP53 mutation could reprogram neighboring TAMs into pro-tumor state via secreting miR-1246-enriched exosomes [131]. After uptake of exosomal miR-1246, TAMs exhibited higher immunosuppression activity with upregulated TGF-β production [131]. Notably, it was reported that epigallocatechin gallate increased the level of miR-16 in breast cancer cells (4T1 cells) which could be further transferred into TAMs by exosomes and decreased the abundance of M2-like TAMs [132].

Cancer-derived exosomal miRNAs and MDSCs

Accumulating evidence has indicated that cancer-derived exosomal miRNAs are capable of regulating the abundance and function of MDSCs [144]. Ren et al. reported that gastric cancer cells enhanced the expansion and activity of MDSCs by delivering miRNA-107-enriched exosomes [133]. Similarly, in the condition of hypoxia, glioma secreted exosomal miR-29a and miR-92a which enhanced the proliferation and function of MDSCs via targeting Hbp1 as well as Prkar1a [136]. Besides, this hypoxia-induced glioma could generate exosomal miR-10a and miR-21 to propel the expansion and activation of MDSCs [135]. Additionally, it was found that oral squamous cell carcinoma-derived exosomal miR-21 activated the downstream PTEN-PD-L1 pathway in MDSCs, which further enhanced the immune tolerance in the tumor microenvironment [134]. However, this exosomal-mediated MDSCs induction could be interfered by additional vitamin D treatment. Analogously, Bruns et al. found that chronic lymphocytic leukemia-derived miR-155 induced the formation of MDSCs but this process was hampered by vitamin D treatment [137].

Cancer cells-derived exosomal miRNAs and cancer-associated fibroblasts

As the most abundant cells of cancer stroma, cancer-associated fibroblasts (CAFs) secret multiple cytokines and extracellular matrix components such as collagens and fibronectins, which generate a physical barrier separating lymphocytes from tumor and inhibiting the infiltration of effector cells [145]. Hyperactive CAF is an unfavorable prognostic factor for patients receiving immunotherapy [44]. Cancer-derived exosomal miRNA is a vital factor accounting for increased CAFs in the tumor microenvironment. Gastric cancer-derived exosomal miR-27a promoted the transformation from normal fibroblasts toward CAFs [138]. In addition, Fang et al. found that metastatic hepatocellular carcinoma cells produced exosomal miR-1247-3p which could target B4GALT3 and activate β1-integrin-NF-κB signaling pathway in CAFs [139]. Besides, Zhou et al. observed that hepatocellular carcinoma enhanced the activity of CAFs by exosomal miRNA-21-PTEN-PDK1/AKT pathway [140].

The effect of miRNAs on immunotherapy

Due to the substantial influence of some cancer cell-derived miRNAs on anti-cancer immune response, it is promising to develop miRNA-based diagnostic tools and therapeutic applications. In NSCLC mouse models, it was found that miR-34a suppressed PD-L1 expression by binding to its 3′UTR region. Therapeutic injection of liposomal nanoparticles containing miR-34a mimics increased the abundance of TILs and decreased the ratio of PD-1+CD8+ T cells [146]. Theoretically, this miRNA-based treatment is synergistic with following immunotherapies.

In addition, some miRNAs are determinates of efficacy of immune checkpoint inhibitors. Zhang et al. found that circFGFR1 acted as the miRNA sponge of miR-381-3p and induced the therapeutic resistance to PD-1 blockade [147]. Besides, Nakahara et al. reported that the high levels of miR-16-5p, miR-17-5p, and miR-20a-5p were the indicators of responders of melanoma patients receiving anti-PD-1 therapy [148]. Moreover, Zheng et al. observed that miR-155 induced the apoptosis of T cells by Fas-FasL pathway and upregulated the expression of PD-L1 on lymphoma cells. The results of in vivo study showed that the miR-155 overexpressed lymphoma cells were highly sensitive to PD-L1 blockade treatment [149]. More and more evidence suggested that some specific miRNA expression patterns could predict immunotherapy resistance. It was documented that a panel of miRNAs including miR-99b, miR-100, miR-125a/b, and miR-146a/b highly related with treatment resistance to immune checkpoint blockade in melanoma patients. These miRNAs could induce the conversion of myeloid cells to MDSC and herald poor immunotherapy outcomes [150].

Apart from immune checkpoint inhibitors, it has been verified that some miRNAs affect the efficacy of other immunotherapies such as CAR T cells. In xenograft tumor of human colon cancer, miR-153 inhibited the expression of IDO and enhanced the effect of CAR T cells targeting epidermal growth factor receptor [46]. In addition, Zhang et al. found that miR-143 promoted the differentiation of central memory T cells and increased the secretion of cytokines. Further investigation indicated that miR-143 overexpression boosted the specific killing activity of HER2-CAR T cells against TE-7 cells by inhibiting glucose uptake and glycolysis [151].

Perspective and conclusion

Alteration in miRNA expression profile plays an indispensable role in carcinogenesis. Upregulated onco-miRNAs and downregulated tumor-suppressed miRNAs render cancer cells with enhanced viability and invasiveness. We noticed that more and more clinical studies try to predict the patients’ prognosis or treatment efficiency by analyzing miRNA expression profile. It was more refreshing that multiple onco-miRNA-targeted agents had been designed such as miR-RX34 liposomal. Besides, Liang et al. designed an engineered exosome which could deliver chemotherapeutic drugs 5-Fluorouracil and miR-21 inhibitor oligonucleotide to Her2+ colon cancer cells. This co-delivering by exosomes showed potent anti-cancer effect in mouse models and reversed the chemotherapy resistance to 5-Fluorouracil [152]. The efficacy and safety of these novel targeted therapies were undergoing evaluation. The concept of miRNA has a profound implication in understanding numerous cancer malignant biological behaviors.

Apart from participating carcinogenesis, some specific miRNA expression pattern could predict cancer immune evasion. We proposed that it would be feasible to utilize miRNA expression profiles and other parameters to construct a comprehensive framework for evaluating patients’ immune state. This evaluation is meaningful to determine further treatment options. Besides, normalizing these immunosuppressive miRNA expression patterns might have a synergistic effect with simultaneous immunotherapy.

Availability of data and materials

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.



3′-untranslated region


Antigen presentation cells




Antigen processing machinery


Cancer-associated fibroblast


Chimeric antigen receptor


Cytotoxic T lymphocyte


G-protein-coupled estrogen receptor-1


Human leukocyte antigen


Indoleamine 2, 3-dioxygenase






Inducible nitric oxide synthase


Proteasome subunits latent membrane protein


Myeloid-derived suppressor cell


Major histocompatibility complex class I


MHC-I chain-related molecules A/B


Non-small cell lung cancer


Sh2 domain containing inositol phosphatase-1


Suppressor of cytokine signaling 1


Tumor-associated macrophage


Transforming growth factor-β


Tumor-infiltrating lymphocyte


T cell immunoglobulin and mucin domain-containing protein 3


UL16-binding protein


V-domain Ig suppressor of T cell activation


Tumor-associated antigen


Transporter associated with antigen processing


T cell immunoreceptor with Ig and ITIM domains


  1. 1.

    Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10.

    Article  CAS  Google Scholar 

  2. 2.

    Yi M, Qin S, Zhao W, Yu S, Chu Q, Wu K. The role of neoantigen in immune checkpoint blockade therapy. Exp Hematol Oncol. 2018;7:28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Metelli A, Salem M, Wallace CH, Wu BX, Li A, Li X, et al. Immunoregulatory functions and the therapeutic implications of GARP-TGF-beta in inflammation and cancer. J Hematol Oncol. 2018;11:24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27:1492–504.

    Article  CAS  Google Scholar 

  5. 5.

    Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;35(Suppl):S185–98.

    Article  CAS  Google Scholar 

  6. 6.

    Alissafi T, Hatzioannou A, Legaki AI, Varveri A, Verginis P. Balancing cancer immunotherapy and immune-related adverse events: The emerging role of regulatory T cells. J Autoimmun. 2019;104:102310.

    Article  CAS  Google Scholar 

  7. 7.

    Marin-Acevedo JA, Soyano AE, Dholaria B, Knutson KL, Lou Y. Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol. 2018;11:8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018;378:1789–801.

    Article  CAS  Google Scholar 

  9. 9.

    Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. 2018;378:1976–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Wang D, Lin J, Yang X, Long J, Bai Y, Yang X, et al. Combination regimens with PD-1/PD-L1 immune checkpoint inhibitors for gastrointestinal malignancies. J Hematol Oncol. 2019;12:42.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321–30.

    Article  CAS  Google Scholar 

  12. 12.

    Lan Y, Zhang D, Xu C, Hance KW, Marelli B, Qi J, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-beta. Sci Transl Med. 2018.

  13. 13.

    Wu CJ, Lu LF. MicroRNA in Immune regulation. Curr Top Microbiol Immunol. 2017;410:249–67.

    CAS  PubMed  Google Scholar 

  14. 14.

    Marzagalli M, Ebelt ND, Manuel ER. Unraveling the crosstalk between melanoma and immune cells in the tumor microenvironment. Semin Cancer Biol. 2019;59:236–50.

    Article  CAS  Google Scholar 

  15. 15.

    Leichter AL, Sullivan MJ, Eccles MR, Chatterjee A. MicroRNA expression patterns and signalling pathways in the development and progression of childhood solid tumours. Mol Cancer. 2017;16:15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Chen J, Zhou R, Liang Y, Fu X, Wang D, Wang C. Blockade of lncRNA-ASLNCS5088-enriched exosome generation in M2 macrophages by GW4869 dampens the effect of M2 macrophages on orchestrating fibroblast activation. FASEB J. 2019;33:12200–12.

    Article  CAS  Google Scholar 

  17. 17.

    Liu X, Luo M, Meng H, Zeng Q, Xu L, Hu B, et al. MiR-181a regulates CD4(+) T cell activation and differentiation by targeting IL-2 in the pathogenesis of myasthenia gravis. Eur J Immunol. 2019.

  18. 18.

    Goncalves-Alves E, Saferding V, Schliehe C, Benson R, Kurowska-Stolarska M, Brunner JS, et al. MicroRNA-155 Controls T Helper Cell Activation During Viral Infection. Front Immunol. 2019;10:1367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Fleshner M, Crane CR. Exosomes, DAMPs and miRNA: features of stress physiology and immune homeostasis. Trends Immunol. 2017;38:768–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Chang YY, Kuo WH, Hung JH, Lee CY, Lee YH, Chang YC, et al. Deregulated microRNAs in triple-negative breast cancer revealed by deep sequencing. Mol Cancer. 2015;14:36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Wang WT, Han C, Sun YM, Chen TQ, Chen YQ. Noncoding RNAs in cancer therapy resistance and targeted drug development. J Hematol Oncol. 2019;12:55.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Ni SJ, Zhao LQ, Wang XF, Wu ZH, Hua RX, Wan CH, et al. CBX7 regulates stem cell-like properties of gastric cancer cells via p16 and AKT-NF-kappaBmiR-21 pathways. J Hematol Oncol. 2018;11:17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Sun Z, Shi K, Yang S, Liu J, Zhou Q, Wang G, et al. Effect of exosomal miRNA on cancer biology and clinical applications. Mol Cancer. 2018;17:147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Eichmuller SB, Osen W, Mandelboim O, Seliger B. Immune modulatory microRNAs Involved in tumor attack and tumor immune escape. J Natl Cancer Inst. 2017.

  25. 25.

    Arrieta VA, Cacho-Diaz B, Zhao J, Rabadan R, Chen L, Sonabend AM. The possibility of cancer immune editing in gliomas. A critical review. Oncoimmunology. 2018;7:e1445458.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.

    Article  CAS  Google Scholar 

  27. 27.

    Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137–48.

    Article  CAS  Google Scholar 

  28. 28.

    Saleh R, Elkord E. Acquired resistance to cancer immunotherapy: Role of tumor-mediated immunosuppression. Semin Cancer Biol. 2019.

  29. 29.

    Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells. Immunology. 2006;117:433–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Liu F, Liu Y, Chen Z. Tim-3 expression and its role in hepatocellular carcinoma. J Hematol Oncol. 2018;11:126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014;40:569–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Wang L, Rubinstein R, Lines JL, Wasiuk A, Ahonen C, Guo Y, et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med. 2011;208:577–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Marin-Acevedo JA, Dholaria B, Soyano AE, Knutson KL, Chumsri S, Lou Y. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol. 2018;11:39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Saleh R, Elkord E. Treg-mediated acquired resistance to immune checkpoint inhibitors. Cancer Lett. 2019;457:168–79.

    Article  CAS  Google Scholar 

  35. 35.

    Achour A, Simon Q, Mohr A, Seite JF, Youinou P, Bendaoud B, et al. Human regulatory B cells control the TFH cell response. J Allergy Clin Immunol. 2017;140:215–22.

    Article  CAS  Google Scholar 

  36. 36.

    Khan AR, Hams E, Floudas A, Sparwasser T, Weaver CT, Fallon PG. PD-L1hi B cells are critical regulators of humoral immunity. Nat Commun. 2015;6:5997.

    Article  CAS  Google Scholar 

  37. 37.

    Fehres CM, van Uden NO, Yeremenko NG, Fernandez L, Franco Salinas G, van Duivenvoorde LM, et al. APRIL Induces a Novel Subset of IgA(+) Regulatory B Cells That Suppress Inflammation via Expression of IL-10 and PD-L1. Front Immunol. 2019;10:1368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Liu Y, Wei G, Cheng WA, Dong Z, Sun H, Lee VY, et al. Targeting myeloid-derived suppressor cells for cancer immunotherapy. Cancer Immunol Immunother. 2018;67:1181–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med. 2007;13:828–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Lin Y, Xu J, Lan H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol. 2019;12:76.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Restifo NP, Esquivel F, Kawakami Y, Yewdell JW, Mule JJ, Rosenberg SA, et al. Identification of human cancers deficient in antigen processing. J Exp Med. 1993;177:265–72.

    Article  CAS  Google Scholar 

  43. 43.

    Travis MA, Sheppard D. TGF-beta activation and function in immunity. Annu Rev Immunol. 2014;32:51–82.

    Article  CAS  Google Scholar 

  44. 44.

    Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Yi M, Jiao D, Qin S, Chu Q, Wu K, Li A. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol Cancer. 2019;18:60.

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Huang Q, Xia J, Wang L, Wang X, Ma X, Deng Q, et al. miR-153 suppresses IDO1 expression and enhances CAR T cell immunotherapy. J Hematol Oncol. 2018;11:58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Mondanelli G, Ugel S, Grohmann U, Bronte V. The immune regulation in cancer by the amino acid metabolizing enzymes ARG and IDO. Curr Opin Pharmacol. 2017;35:30–9.

    Article  CAS  Google Scholar 

  48. 48.

    Bradford JW, Baldwin AS. IKK/nuclear factor-kappaB and oncogenesis: roles in tumor-initiating cells and in the tumor microenvironment. Adv Cancer Res. 2014;121:125–45.

    Article  CAS  Google Scholar 

  49. 49.

    Omar HA, El-Serafi AT, Hersi F, Arafa EA, Zaher DM, Madkour M, et al. Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment. FEBS J. 2019;286:3540–57.

    Article  CAS  Google Scholar 

  50. 50.

    Seliger B. Immune modulatory microRNAs as a novel mechanism to revert immune escape of tumors. Cytokine Growth Factor Rev. 2017;36:49–56.

    Article  CAS  Google Scholar 

  51. 51.

    Whiteside TL. The effect of tumor-derived exosomes on immune regulation and cancer immunotherapy. Future Oncol. 2017;13:2583–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Moore C, Kosgodage U, Lange S, Inal JM. The emerging role of exosome and microvesicle- (EMV-) based cancer therapeutics and immunotherapy. Int J Cancer. 2017;141:428–36.

    Article  CAS  Google Scholar 

  53. 53.

    Gao F, Zhao ZL, Zhao WT, Fan QR, Wang SC, Li J, et al. miR-9 modulates the expression of interferon-regulated genes and MHC class I molecules in human nasopharyngeal carcinoma cells. Biochem Biophys Res Commun. 2013;431:610–6.

    Article  CAS  Google Scholar 

  54. 54.

    Mari L, Hoefnagel SJM, Zito D, van de Meent M, van Endert P, Calpe S, et al. microRNA 125a Regulates MHC-I Expression on Esophageal Adenocarcinoma Cells, Associated With Suppression of Antitumor Immune Response and Poor Outcomes of Patients. Gastroenterology. 2018;155:784–98.

    Article  CAS  Google Scholar 

  55. 55.

    Yin P, Peng R, Peng H, Yao L, Sun Y, Wen L, et al. MiR-451 suppresses cell proliferation and metastasis in A549 lung cancer cells. Mol Biotechnol. 2015;57:1–11.

    Article  CAS  Google Scholar 

  56. 56.

    Colangelo T, Polcaro G, Ziccardi P, Pucci B, Muccillo L, Galgani M, et al. Proteomic screening identifies calreticulin as a miR-27a direct target repressing MHC class I cell surface exposure in colorectal cancer. Cell Death Dis. 2016;7:e2120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Park S, Eom K, Kim J, Bang H, Wang HY, Ahn S, et al. MiR-9, miR-21, and miR-155 as potential biomarkers for HPV positive and negative cervical cancer. BMC Cancer. 2017;17:658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Han L, Wang W, Ding W, Zhang L. MiR-9 is involved in TGF-beta1-induced lung cancer cell invasion and adhesion by targeting SOX7. J Cell Mol Med. 2017;21:2000–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Chen X, Yang F, Zhang T, Wang W, Xi W, Li Y, et al. MiR-9 promotes tumorigenesis and angiogenesis and is activated by MYC and OCT4 in human glioma. J Exp Clin Cancer Res. 2019;38:99.

    Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Bartoszewski R, Brewer JW, Rab A, Crossman DK, Bartoszewska S, Kapoor N, et al. The unfolded protein response (UPR)-activated transcription factor Xbox-binding protein 1 (XBP1) induces microRNA-346 expression that targets the human antigen peptide transporter 1 (TAP1) mRNA and governs immune regulatory genes. J Biol Chem. 2011;286:41862–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Ferreira LMR, Meissner TB, Tilburgs T, Strominger JL. HLA-G: At the Interface of Maternal-Fetal Tolerance. Trends Immunol. 2017;38:272–86.

    Article  CAS  Google Scholar 

  62. 62.

    Carosella ED, Rouas-Freiss N, Tronik-Le Roux D, Moreau P, LeMaoult J. HLA-G: an immune checkpoint molecule. Adv Immunol. 2015;127:33–144.

    Article  CAS  Google Scholar 

  63. 63.

    Paul P, Rouas-Freiss N, Khalil-Daher I, Moreau P, Riteau B, Le Gal FA, et al. HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. Proc Natl Acad Sci U S A. 1998;95:4510–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Yan WH. Human leukocyte antigen-G in cancer: are they clinically relevant? Cancer Lett. 2011;311:123–30.

    Article  CAS  Google Scholar 

  65. 65.

    Manaster I, Goldman-Wohl D, Greenfield C, Nachmani D, Tsukerman P, Hamani Y, et al. MiRNA-mediated control of HLA-G expression and function. PLoS One. 2012;7:e33395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Jasinski-Bergner S, Stehle F, Gonschorek E, Kalich J, Schulz K, Huettelmaier S, et al. Identification of 14-3-3beta gene as a novel miR-152 target using a proteome-based approach. J Biol Chem. 2014;289:31121–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Zhu XM, Han T, Wang XH, Li YH, Yang HG, Luo YN, et al. Overexpression of miR-152 leads to reduced expression of human leukocyte antigen-G and increased natural killer cell mediated cytolysis in JEG-3 cells. Am J Obstet Gynecol. 2010;202:592.e1–7.

    Article  CAS  Google Scholar 

  68. 68.

    Tao S, He H, Chen Q, Yue W. GPER mediated estradiol reduces miR-148a to promote HLA-G expression in breast cancer. Biochem Biophys Res Commun. 2014;451:74–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Wang X, Li B, Wang J, Lei J, Liu C, Ma Y, et al. Evidence that miR-133a causes recurrent spontaneous abortion by reducing HLA-G expression. Reprod BioMed Online. 2012;25:415–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Schmiedel D, Mandelboim O. NKG2D Ligands-critical targets for cancer immune escape and therapy. Front Immunol. 2018;9:2040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Yadav D, Ngolab J, Lim RS, Krishnamurthy S, Bui JD. Cutting edge: down-regulation of MHC class I-related chain A on tumor cells by IFN-gamma-induced microRNA. J Immunol. 2009;182:39–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Stern-Ginossar N, Gur C, Biton M, Horwitz E, Elboim M, Stanietsky N, et al. Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nat Immunol. 2008;9:1065–73.

    Article  CAS  Google Scholar 

  73. 73.

    Zhang J, Basher F, Wu JD. NKG2D ligands in tumor immunity: two sides of a coin. Front Immunol. 2015;6:97.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Xie J, Liu M, Li Y, Nie Y, Mi Q, Zhao S. Ovarian tumor-associated microRNA-20a decreases natural killer cell cytotoxicity by downregulating MICA/B expression. Cell Mol Immunol. 2014;11:495–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Wu J, Zhang XJ, Shi KQ, Chen YP, Ren YF, Song YJ, et al. Hepatitis B surface antigen inhibits MICA and MICB expression via induction of cellular miRNAs in hepatocellular carcinoma cells. Carcinogenesis. 2014;35:155–63.

    Article  CAS  Google Scholar 

  76. 76.

    Yang H, Lan P, Hou Z, Guan Y, Zhang J, Xu W, et al. Histone deacetylase inhibitor SAHA epigenetically regulates miR-17-92 cluster and MCM7 to upregulate MICA expression in hepatoma. Br J Cancer. 2015;112:112–21.

    Article  CAS  Google Scholar 

  77. 77.

    Shen J, Pan J, Du C, Si W, Yao M, Xu L, et al. Silencing NKG2D ligand-targeting miRNAs enhances natural killer cell-mediated cytotoxicity in breast cancer. Cell Death Dis. 2017;8:e2740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Tang S, Fu H, Xu Q, Zhou Y. miR-20a regulates sensitivity of colorectal cancer cells to NK cells by targeting MICA. Biosci Rep. 2019.

  79. 79.

    Shekari N, Javadian M, Ghaffari S, Baradaran B, Darabi M, Kazemi T. DHA Abolishes the Detrimental Effect of Docetaxel on Downregulation of the MICA via Decreasing the Expression Level of MicroRNA-20a in Gastric Cancer. J Gastrointest Cancer. 2019.

  80. 80.

    Kishikawa T, Otsuka M, Yoshikawa T, Ohno M, Takata A, Shibata C, et al. Regulation of the expression of the liver cancer susceptibility gene MICA by microRNAs. Sci Rep. 2013;3:2739.

    Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Breunig C, Pahl J, Kublbeck M, Miller M, Antonelli D, Erdem N, et al. MicroRNA-519a-3p mediates apoptosis resistance in breast cancer cells and their escape from recognition by natural killer cells. Cell Death Dis. 2017;8:e2973.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Abruzzese MP, Bilotta MT, Fionda C, Zingoni A, Soriani A, Vulpis E, et al. Inhibition of bromodomain and extra-terminal (BET) proteins increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of cMYC-IRF4-miR-125b interplay. J Hematol Oncol. 2016;9:134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Min D, Lv XB, Wang X, Zhang B, Meng W, Yu F, et al. Downregulation of miR-302c and miR-520c by 1,25(OH)2D3 treatment enhances the susceptibility of tumour cells to natural killer cell-mediated cytotoxicity. Br J Cancer. 2013;109:723–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Ou ZL, Luo Z, Wei W, Liang S, Gao TL, Lu YB. Hypoxia-induced shedding of MICA and HIF1A-mediated immune escape of pancreatic cancer cells from NK cells: role of circ_0000977/miR-153 axis. RNA Biol. 2019:1–12.

  85. 85.

    Yi M, Jiao D, Xu H, Liu Q, Zhao W, Han X, et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer. 2018;17:129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Li D, Wang X, Yang M, Kan Q, Duan Z. miR3609 sensitizes breast cancer cells to adriamycin by blocking the programmed death-ligand 1 immune checkpoint. Exp Cell Res. 2019;380:20–8.

    Article  CAS  Google Scholar 

  87. 87.

    Zhou WY, Zhang MM, Liu C, Kang Y, Wang JO, Yang XH. Long noncoding RNA LINC00473 drives the progression of pancreatic cancer via upregulating programmed death-ligand 1 by sponging microRNA-195-5p. J Cell Physiol. 2019;234:23176–89.

    Article  CAS  Google Scholar 

  88. 88.

    Ashizawa M, Okayama H, Ishigame T, Thar Min AK, Saito K, Ujiie D, et al. miRNA-148a-3p Regulates Immunosuppression in DNA Mismatch Repair- Deficient Colorectal Cancer by Targeting PD-L1. Mol Cancer Res. 2019;17:1403–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Gao L, Guo Q, Li X, Yang X, Ni H, Wang T, et al. MiR-873/PD-L1 axis regulates the stemness of breast cancer cells. EBioMedicine. 2019;41:395–407.

    Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Qu F, Ye J, Pan X, Wang J, Gan S, Chu C, et al. MicroRNA-497-5p down-regulation increases PD-L1 expression in clear cell renal cell carcinoma. J Drug Target. 2019;27:67–74.

    Article  CAS  Google Scholar 

  91. 91.

    Chen XY, Zhang J, Hou LD, Zhang R, Chen W, Fan HN, et al. Upregulation of PD-L1 predicts poor prognosis and is associated with miR-191-5p dysregulation in colon adenocarcinoma. Int J Immunopathol Pharmacol. 2018;32:2058738418790318.

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Anastasiadou E, Stroopinsky D, Alimperti S, et al. Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas. Leukemia. 2019;33:132–47.

    Article  CAS  Google Scholar 

  93. 93.

    Wang Y, Wang L. miR-34a attenuates glioma cells progression and chemoresistance via targeting PD-L1. Biotechnol Lett. 2017;39:1485–92.

    Article  CAS  Google Scholar 

  94. 94.

    Zhang XL, Xu LL, Wang F. Hsa_circ_0020397 regulates colorectal cancer cell viability, apoptosis and invasion by promoting the expression of the miR-138 targets TERT and PD-L1. Cell Biol Int. 2017;41:1056–64.

    Article  CAS  Google Scholar 

  95. 95.

    Dong P, Xiong Y, Yu J, Chen L, Tao T, Yi S, et al. Control of PD-L1 expression by miR-140/142/340/383 and oncogenic activation of the OCT4-miR-18a pathway in cervical cancer. Oncogene. 2018;37:5257–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Kao SC, Cheng YY, Williams M, Kirschner MB, Madore J, Lum T, et al. Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma. J Thorac Oncol. 2017;12:1421–33.

    Article  Google Scholar 

  97. 97.

    Tang D, Zhao D, Wu Y, Yao R, Zhou L, Lu L, et al. The miR-3127-5p/p-STAT3 axis up-regulates PD-L1 inducing chemoresistance in non-small-cell lung cancer. J Cell Mol Med. 2018.

  98. 98.

    Tao Z, Xu S, Ruan H, Wang T, Song W, Qian L, et al. MiR-195/-16 Family Enhances Radiotherapy via T Cell Activation in the Tumor Microenvironment by Blocking the PD-L1 Immune Checkpoint. Cell Physiol Biochem. 2018;48:801–14.

    Article  CAS  Google Scholar 

  99. 99.

    He B, Yan F, Wu C. Overexpressed miR-195 attenuated immune escape of diffuse large B-cell lymphoma by targeting PD-L1. Biomed Pharmacother. 2018;98:95–101.

    Article  CAS  Google Scholar 

  100. 100.

    Mastroianni J, Stickel N, Andrlova H, Hanke K, Melchinger W, Duquesne S, et al. miR-146a Controls Immune Response in the Melanoma Microenvironment. Cancer Res. 2019;79:183–95.

    Article  CAS  Google Scholar 

  101. 101.

    Pyzer AR, Stroopinsky D, Rosenblatt J, Anastasiadou E, Rajabi H, Washington A, et al. MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs. Leukemia. 2017;31:2780–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Wang X, Li J, Dong K, Lin F, Long M, Ouyang Y, et al. Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cell Signal. 2015;27:443–52.

    Article  CAS  Google Scholar 

  103. 103.

    Xie WB, Liang LH, Wu KG, Wang LX, He X, Song C, et al. MiR-140 Expression Regulates Cell Proliferation and Targets PD-L1 in NSCLC. Cell Physiol Biochem. 2018;46:654–63.

    Article  CAS  Google Scholar 

  104. 104.

    Wan J, Ling X, Peng B, Ding G. miR-142-5p regulates CD4+ T cells in human non-small cell lung cancer through PD-L1 expression via the PTEN pathway. Oncol Rep. 2018;40:272–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Jia L, Xi Q, Wang H, Zhang Z, Liu H, Cheng Y, et al. miR-142-5p regulates tumor cell PD-L1 expression and enhances anti-tumor immunity. Biochem Biophys Res Commun. 2017;488:425–31.

    Article  CAS  Google Scholar 

  106. 106.

    Chen L, Gibbons DL, Goswami S, Cortez MA, Ahn YH, Byers LA, et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PDL1 expression and intratumoral immunosuppression. Nat Commun. 2014;5:5241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Sun C, Lan P, Han Q, Huang M, Zhang Z, Xu G, et al. Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion. Nat Commun. 2018;9:1241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Wu Q, Zhao Y, Sun Y, Yan X, Wang P. miR-375 inhibits IFN-gamma-induced programmed death 1 ligand 1 surface expression in head and neck squamous cell carcinoma cells by blocking JAK2/STAT1 signaling. Oncol Rep. 2018;39:1461–8.

    CAS  PubMed  Google Scholar 

  109. 109.

    Zhao L, Yu H, Yi S, Peng X, Su P, Xiao Z, et al. The tumor suppressor miR-138-5p targets PD-L1 in colorectal cancer. Oncotarget. 2016;7:45370–84.

    PubMed  PubMed Central  Google Scholar 

  110. 110.

    Cioffi M, Trabulo SM, Vallespinos M, Raj D, Kheir TB, Lin ML, et al. The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1. Oncotarget. 2017;8:21609–25.

    Article  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Audrito V, Serra S, Stingi A, Orso F, Gaudino F, Bologna C, et al. PD-L1 up-regulation in melanoma increases disease aggressiveness and is mediated through miR-17-5p. Oncotarget. 2017;8:15894–911.

    Article  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Fujita Y, Yagishita S, Hagiwara K, Yoshioka Y, Kosaka N, Takeshita F, et al. The clinical relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer. Mol Ther. 2015;23:717–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Abrahams VM, Kamsteeg M, Mor G. The Fas/Fas ligand system and cancer: immune privilege and apoptosis. Mol Biotechnol. 2003;25:19–30.

    Article  CAS  Google Scholar 

  114. 114.

    Kim R, Emi M, Tanabe K, Arihiro K. Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res. 2006;66:5527–36.

    Article  CAS  Google Scholar 

  115. 115.

    Mariotti B, Calabretto G, Rossato M, Teramo A, Castellucci M, Barila G, et al. Identification of a miR-146b-FasL axis in the development of neutropenia in T large granular lymphocyte leukemia. Haematologica. 2019.

  116. 116.

    Xie Z, Chen W, Chen Y, Wang X, Gao W, Liu Y. miR-768-3p is involved in the proliferation, invasion and migration of non-small cell lung carcinomas. Int J Oncol. 2017;51:1574–82.

    Article  CAS  Google Scholar 

  117. 117.

    Wu MF, Yang J, Xiang T, Shi YY, Liu LJ. miR-21 targets Fas ligand-mediated apoptosis in breast cancer cell line MCF-7. J Huazhong Univ Sci Technolog Med Sci. 2014;34:190–4.

    Article  CAS  Google Scholar 

  118. 118.

    Wang N, Zhang CQ, He JH, Duan XF, Wang YY, Ji X, et al. MiR-21 down-regulation suppresses cell growth, invasion and induces cell apoptosis by targeting FASL, TIMP3, and RECK genes in esophageal carcinoma. Dig Dis Sci. 2013;58:1863–70.

    Article  CAS  Google Scholar 

  119. 119.

    Wang P, Zhuang L, Zhang J, Fan J, Luo J, Chen H, et al. The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL. Mol Oncol. 2013;7:334–45.

    Article  CAS  Google Scholar 

  120. 120.

    Wang K, Li PF. Foxo3a regulates apoptosis by negatively targeting miR-21. J Biol Chem. 2010;285:16958–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Cheong JE, Sun L. Targeting the IDO1/TDO2-KYN-AhR pathway for cancer immunotherapy—challenges and opportunities. Trends Pharmacol Sci. 2018;39:307–25.

    Article  CAS  Google Scholar 

  122. 122.

    Gunther J, Dabritz J, Wirthgen E. Limitations and off-target effects of tryptophan-related IDO Inhibitors in cancer treatment. Front Immunol. 2019;10:1801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Zhu L, Tu H, Liang Y, Tang D. MiR-218 produces anti-tumor effects on cervical cancer cells in vitro. World J Surg Oncol. 2018;16:204.

    Article  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Lou Q, Liu R, Yang X, Li W, Huang L, Wei L, et al. miR-448 targets IDO1 and regulates CD8(+) T cell response in human colon cancer. J Immunother. Cancer. 2019;7:210.

    Google Scholar 

  125. 125.

    Zhou J, Yang Y, Wang W, Zhang Y, Chen Z, Hao C, et al. Melanoma-released exosomes directly activate the mitochondrial apoptotic pathway of CD4(+) T cells through their microRNA cargo. Exp Cell Res. 2018;371:364–71.

    Article  CAS  Google Scholar 

  126. 126.

    Ye SB, Li ZL, Luo DH, Huang BJ, Chen YS, Zhang XS, et al. Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma. Oncotarget. 2014;5:5439–52.

    Article  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Ying X, Wu Q, Wu X, Zhu Q, Wang X, Jiang L, et al. Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages. Oncotarget. 2016;7:43076–87.

    PubMed  PubMed Central  Google Scholar 

  128. 128.

    Chen X, Ying X, Wang X, Wu X, Zhu Q, Wang X. Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization. Oncol Rep. 2017;38:522–8.

    Article  CAS  Google Scholar 

  129. 129.

    Chen X, Zhou J, Li X, Wang X, Lin Y, Wang X. Exosomes derived from hypoxic epithelial ovarian cancer cells deliver microRNAs to macrophages and elicit a tumor-promoted phenotype. Cancer Lett. 2018;435:80–91.

    Article  CAS  Google Scholar 

  130. 130.

    Hsieh CH, Tai SK, Yang MH. Snail-overexpressing cancer cells promote M2-like polarization of tumor-associated macrophages by delivering MiR-21- Abundant exosomes. Neoplasia. 2018;20:775–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Cooks T, Pateras IS, Jenkins LM, Patel KM, Robles AI, Morris J, et al. Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nat Commun. 2018;9:771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Jang JY, Lee JK, Jeon YK, Kim CW. Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumorassociated macrophage infiltration and M2 polarization. BMC Cancer. 2013;13:421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Ren W, Zhang X, Li W, Feng Q, Feng H, Tong Y, et al. Exosomal miRNA-107 induces myeloid-derived suppressor cell expansion in gastric cancer. Cancer Manag Res. 2019;11:4023–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Li L, Cao B, Liang X, Lu S, Luo H, Wang Z, et al. Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral gammadelta T cell equilibrium via tumor-derived exosomes. Oncogene. 2019;38:2830–43.

    Article  CAS  Google Scholar 

  135. 135.

    Guo X, Qiu W, Liu Q, Qian M, Wang S, Zhang Z, et al. Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten Pathways. Oncogene. 2018;37:4239–59.

    Article  CAS  Google Scholar 

  136. 136.

    Guo X, Qiu W, Wang J, Liu Q, Qian M, Wang S, et al. Glioma exosomes mediate the expansion and function of myeloid-derived suppressor cells through microRNA-29a/Hbp1 and microRNA-92a/Prkar1a pathways. Int J Cancer. 2019;144:3111–26.

    Article  CAS  Google Scholar 

  137. 137.

    Bruns H, Bottcher M, Qorraj M, Fabri M, Jitschin S, Dindorf J, et al. CLL-cell-mediated MDSC induction by exosomal miR-155 transfer is disrupted by vitamin D. Leukemia. 2017;31:985–8.

    Article  CAS  Google Scholar 

  138. 138.

    Wang J, Guan X, Zhang Y, Ge S, Zhang L, Li H, et al. Exosomal miR-27a Derived from Gastric Cancer Cells Regulates the Transformation of Fibroblasts into Cancer-Associated Fibroblasts. Cell Physiol Biochem. 2018;49:869–83.

    Article  CAS  Google Scholar 

  139. 139.

    Fang T, Lv H, Lv G, Li T, Wang C, Han Q, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun. 2018;9:191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Zhou Y, Ren H, Dai B, Li J, Shang L, Huang J, et al. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts. J Exp Clin Cancer Res. 2018;37:324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Fanini F, Fabbri M. Cancer-derived exosomic microRNAs shape the immune system within the tumor microenvironment: State of the art. Semin Cell Dev Biol. 2017;67:23–8.

    Article  CAS  Google Scholar 

  142. 142.

    Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol. 2017;10:58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Brown JM, Recht L, Strober S. The promise of targeting macrophages in cancer therapy. Clin Cancer Res. 2017;23:3241–50.

    Article  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Tian X, Shen H, Li Z, Wang T, Wang S. Tumor-derived exosomes, myeloid-derived suppressor cells, and tumor microenvironment. J Hematol Oncol. 2019;12:84.

    Article  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Truffi M, Mazzucchelli S, Bonizzi A, Sorrentino L, Allevi R, Vanna R, et al. Nano-Strategies to Target Breast Cancer-Associated Fibroblasts: Rearranging the Tumor Microenvironment to Achieve Antitumor Efficacy. Int J Mol Sci. 2019.

  146. 146.

    Cortez MA, Ivan C, Valdecanas D, Wang X, Peltier HJ, Ye Y, et al. PDL1 Regulation by p53 via miR-34. J Natl Cancer Inst. 2016.

  147. 147.

    Zhang PF, Pei X, Li KS, Jin LN, Wang F, Wu J, et al. Circular RNA circFGFR1 promotes progression and anti-PD-1 resistance by sponging miR-381-3p in non-small cell lung cancer cells. Mol Cancer. 2019;18:179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Nakahara S, Fukushima S, Okada E, Morinaga J, Kubo Y, Tokuzumi A, et al. MicroRNAs that predict the effectiveness of anti-PD-1 therapies in patients with advanced melanoma. J Dermatol Sci. 2020;97:77–9.

    Article  CAS  Google Scholar 

  149. 149.

    Zheng Z, Sun R, Zhao HJ, Fu D, Zhong HJ, Weng XQ, et al. MiR155 sensitized B-lymphoma cells to anti-PD-L1 antibody via PD-1/PD-L1-mediated lymphoma cell interaction with CD8+T cells. Mol Cancer. 2019;18:54.

    Article  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Huber V, Vallacchi V, Fleming V, Hu X, Cova A, Dugo M, et al. Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma. J Clin Invest. 2018;128:5505–16.

    Article  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Zhang T, Zhang Z, Li F, Ping Y, Qin G, Zhang C, et al. miR-143 Regulates Memory T Cell Differentiation by Reprogramming T Cell Metabolism. J Immunol. 2018;201:2165–75.

    Article  CAS  Google Scholar 

  152. 152.

    Liang G, Zhu Y, Ali DJ, Tian T, Xu H, Si K, et al. Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer. J Nanobiotechnology. 2020;18:10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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We thank Drs. Shuang Qin and Tianye Li of Tongji Hospital for helpful discussion and language editing assistance.


This work was supported by the National Natural Science Foundation of China (No. 81874120, 81572608), Wuhan Science and Technology Bureau (No. 2017060201010170), Henan science and technology open cooperation project (No. 162106000021).

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Correspondence to Kongming Wu.

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Yi, M., Xu, L., Jiao, Y. et al. The role of cancer-derived microRNAs in cancer immune escape. J Hematol Oncol 13, 25 (2020).

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  • microRNA
  • Cancer immune surveillance
  • Immune escape
  • Immunotherapy
  • Tumor microenvironment
  • Exosome