Table 2 Other predictive markers of immunotherapy efficacy

Positive Biomarkers

POLD1 mt

POLD1 gene encodes p125, the catalytic subunit of DNA polymerase δ. The polymerase activity and exonuclease function of DNA polymerase δ are concentrated in the p125 subunit, so the POLD1 gene is significantly involved in cell cycle regulation and DNA damage repair [156, 170]. CRC patients with POLD1 mutation often have the characteristics of microsatellite instability, suggesting that patients with POLD1 mutation may benefit from immunotherapy [159]

CDK12-Deficiency

CDK12 inactivation in prostate cancer is related to tandem genomic replication. CDK12 mutation may produce fusion related neoantigens and trigger an immune response, indicating that patients can benefit from ICB therapy [171, 172]

CDKN2A mt

CDKN2A is a tumor suppressor gene that induces cell cycle arrest in the G1 and G2 phases; it also suppresses the oncogenic action of CDK4/6 and MDM2 [173]. Tumors with JAK2 mutations or homozygous JAK2 deletions demonstrate allelic losses covering both the CDKN2A and JAK2 genes^. [174]

SERPINB3/4 mt

SERPINB3/4 mutations are able to enhance tumor neoantigen presentation. The results of a clinical study suggested that melanoma patients carrying SERPINB3/4 mutations could gain better benefit from treatment with CTLA4 antibodies [175]. In the clinical study with code number CA209-038, 68 patients with melanoma were enrolled who had progressed with or without prior to Ipilimumab therapy and received nivolumab. Five of six patients harboring SERPINB3/4 mutations had their disease controlled. However, due to the small sample size, no statistically significant associations between individual gene changes and treatment were found [176]

TP53/KRAS mt

Previous studies have found that in tumors with KRAS/TP53 mutation, the expression levels of PD-L1 and the infiltration of T cells were significantly increased. Patients with TP53, TP53/KRAS and KRAS mutations can benefit from PD-1 inhibitors [177, 178]

DNA DDR Genes mt

ATM, POLE, BRCA2, ERCC2/4, FANCA, CHEK1/2, MLH1/MSH2/MSH1, ATR, BAP1, and RAD belong to DDR genes, which have the function of DNA damage repair. Mutations in the DDR genes may increase the production of tumor neoantigens, resulting in higher tumor mutational burden [179, 180]

Fusobacterium nucleatum

Increased levels of Fusobacterium nucleatum were associated with improved treatment response to PD-L1 blockade [181]

CMTM6

A previous study suggested that CMTM6 expression in M2 macrophages may more accurately predict ICB response in CRC patients than the dMMR/MSI-H state. It can also identify pMMR CRC patients who may benefit from PD-1/PD-L1 inhibitors treatment [182]

NF1 mt

As a GTPase-activating protein, NF1 can downregulate RAS activity, and NF1 mutation can activate the MAPK signaling pathway [183]. In a previous study, patients with NF1 mutations, harboring high mutational burdens and high response rates, could benefit from anti–PD-1 therapy [184]

Negative Biomarkers

MDM2/4

A previous study reported that MDM2/4 amplification could be used as an independent predictor of poor clinical outcome (time-to-treatment failure < 2 months) with immunotherapies. All six (4%) patients with MDM2/MDM4 amplifications indicated explosive progression of the disease. Notably, one of the patients exhibited a high TMB, which was considered as a responsive factor [185]

EGFR mt, ALK mt, MET rearrangement

Several clinical studies have shown that immunotherapy does not perform well in patients with driver gene mutations, such as EGFR and ALK, or patients with MET gene rearrangement, irrespective of the expression level of PD-L1 [186]

STK11 mt

STK11 is a tumor suppressor gene, and its mutations are related to the Peutz-Jeghers syndrome. Previous studies suggested that STK11 mutation can modify the “cold” TME, which was associated with decreased T cell infiltration, increased T cell exhaustion marker expression, and reduction in PD-L1 expression levels [187]. Moreover, the STK11 alteration was considered as a main driver of primary resistance to ICB therapy in KRAS-mutant lung adenocarcinoma samples [188, 189]; An additional study reported that the PFS and OS of the patients with KRAS/STK11 co-mutation who received ICB therapy were significantly lower than those in patients with KRAS mutation and STK11 wild-type patients. The concomitant present of KRAS and STK11 mutations was correlated with a greater risk of HPD following ICI monotherapy [190]

DNMT3A alteration

A previous study reported that in 155 patients, 4 of 5 patients harboring DNMT3A alteration had a hyperprogression (TTF < 2 months) with immunotherapies [185]

Loss of PTEN

PTEN loss was associated with reduction in T cell infiltration in the tumor samples, increased VEGF expression, and inferior outcomes with anti-PD-1 therapy [191]

DKK1

DKK1 inhibits antitumor immune activity of CD8+ T cells through the GSK3β/E2F1/T-bet axis. The increase in the serum expression of DKK1 can predict the poor tumor response to PD-1 blockade in dMMR/MSI CRC, whereas reversal of DKK1 neutralization may restore the sensitivity to PD-1 blockade [192]

LAGE3

High LAGE3 expression is associated with poor prognosis and poor immune infiltration in CRC patients, which suggests a poor immune response in ICB therapy [193]

Circulation LDH Levels

Previous studies have shown that baseline LDH alone or a combination of the LDH levels, performance status, and age were associated with response to ICIs in solid tumors. Another study indicated that LDH baseline levels were an independent indicator of PFS in melanoma patients treated with ICIs by Cox regression analysis [194,195,196]

Increased circulation Tsens

In a clinical study, the number of Tsens at baseline was detected, and patients with relatively high number of Tsens were prone to develop HPD. In contrast to those findings, the tumors subsided significantly in patients with lower Tsens. The results indicated that the number of Tsens in patients prior to immunotherapy could predict the risk of HPD. The baseline number of Tsens may represent the overall situation of a preexisting effector T cell with potential antitumor activity [197]

ILC3

ILC3 was specifically increased in HPD tumors [198]. Immunotherapy for Cancer ILC3s can respond to cytokine stimulation without specific antigen. ILC3 has been shown to produce IL-17 and IL-22, thereby promoting cancer progression [199]. This abnormal inflammatory environment may be related to the adverse efficacy of ICIS

T cell exhaustion

T cell exhaustion is defined as T cell dysfunction, decreased ability to recognize and eliminate antigens, and up regulation the expression levels of the inhibitory receptors, including PD-1, TIM3, TIGIT and LAG-3 [200]. Overexpression of these inhibitory receptors may be the key mechanism of PD-1 treatment resistance. Following the overexpression of these inhibitory receptors, CD8+ T cells indicates serious dysfunction in cytokine production, proliferation and migration [201]

Liver metastasis

Study demonstrated that melanoma patients with liver metastasis response worse than lung metastasis from ICB therapy [202]. MSS mCRC patients with liver metastasis also cannot benefit from the combination of TKI plus ICB [96, 203, 204]