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Table 1 Tumor microenvironment components

From: Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response

Components

Classification

Molecular characteristics

Function in TME

Major Role

Immune cells

T lymphocytes

    

 CD8+ T cell

TME & TIME

CD3+CD8+

Cytotoxicity

Anti-tumoral

 Th1 cell

TME & TIME

CCR6+CXCR3+

Production of IL-2 and IFN-γ

CD8+ T cell supporting

Anti-tumoral

 Th2 cell

TME & TIME

Production of IL-4, IL-5 and IL-13

B cell responses supporting

Pro-tumoral

 Th17 cell

TME & TIME

Production of IL-17A, IL-17F, IL-21, IL-22

Angiogenesis, tumorigenesis, immune regulation

Ambiguous

 Treg cell

TME & TIME

CD4+FOXP3+CD25+

Immune suppression

Pro-tumoral

B lymphocytes

TME & TIME

CD19+CD20+CD138+

Antibody production, antigen presentation, TLSs formation

Anti-tumoral

Innate lymphoid cell (ILCs)

    

 ILC1s

    

  NK cells

TME & TIME

Expression of T-bet; Eomes+ CD27−

Cytotoxic functions without prior sensitization

Anti-tumoral

  Non-NK cells

TME & TIME

Expression of T-bet; Eomes− CD27+

Secretion of IFN-γ and TNF-α to induce tumor dependent anti-tumor immune responses

Ambiguous

 ILC2s

TME & TIME

Expression of GATA3; secretion of type 2 cytokines

Secretion of IL-5, IL-13, IL-4 to inhibit anti-tumor immunity

Pro-tumoral

 ILC3s

TME & TIME

Expression of RORγt

Heterogeneous cells secreting various cytokines and chemokines

Ambiguous

Tumor-associated macrophages

 

HLA-DR+CD68+ CD11c−

  

 M1

TME & TIME

CD86+ CD80+ iNOS+

Promoting anti-tumor TH1 and TH17 immune responses

Anti-tumoral

 M2

TME & TIME

CD163+CD206+

Supporting angiogenesis, tumor progression, and metastasis; immune suppression

Pro-tumoral

MDSCs

TME & TIME

CD11b+HLA-DR−

Differentiating into TAMs, immune suppression

Pro-tumoral

Dendritic cells

TME & TIME

Siglec-H+CD317+

Binary immune regulatory function shaped by TME

Ambiguous

Neutrophils

 

CD14+HLA-DR+CD206−CD86−

  

 N1

TME & TIME

 Supported by TGF-β and G-CSF

Immune respond initiation, antigen presenting

Anti-tumoral

 N2

TME & TIME

 Supported by IFN-γ and hepatocyte growth factor

Remodeling ECM, promoting angiogenesis and tumor growth

Pro-tumoral

Stromal cells

Cancer-associated fibroblasts

TME

Cellular markers: α-SMA, FAP-α, FSP-1/S100A4, PDGFRβ

Promoting tumor cell proliferation and invasion, angiogenesis; ECM remodeling; bidirectional immune regulation

Pro-tumoral

Endothelia cells

TME

Cellular markers: CD31; consisting of blood vessels

Angiogenesis, tumor metastasis

Pro-tumoral

Pericytes

TME

Cellular markers: Calponin, CD90, DLK, NG2, PDGF-A, SMA

Promote primary tumor growth, negative regulator of metastasis,

Pro-tumoral

Adipocytes

TME

Cellular markers: CD34

Secretion of hormones, metabolites, growth factors, enzymes and cytokines

Pro-tumoral

Mesenchymal stem cells

TME

Cellular markers: CD105, CD90, CD117, CD133

Forming the premetastatic niche; promoting tumor initiation and progression

Pro-tumoral

Vessels

Blood vessel

TME

Tubular structures formed by endothelial cells (cellular markers: CD31)

Promoting metastasis and angiogenesis,

Pro-tumoral

Lymph vessel

TME

Tubular structures formed by lymphatic endothelial cells (cellular markers: LYVE-1, Podoplanin, PROX1, VEGFR-3)

Foster tumor metastasis, physical link between lymph nodes and tumor

Pro-tumoral

Extracellular matrix

Collagen, fibronectin, elastin, laminin

TME

Complex noncellular three-dimensional macromolecular network

Physical scaffold for cell, tumor cell dissemination, depot for cytokines and growth factors

Pro-tumoral

Matrix metalloproteases, Cathepsins

TME

Enzymes secreted and activated by malignant cells in extracellular matrix

ECM remodeling, aiding metastasis, angiogenesis and inflammation

Pro-tumoral

Immune molecules

Cytokines

TME & TIME

Mainly secreted by immune cells; acting in a paracrine, autocrine or endocrine manner

Promoting leukocyte growth, survival and activation; promoting tumor immunogenicity, tumor cell proliferation, angiogenesis

Ambiguous, mainly anti-tumoral

Chemokines

TME & TIME

Regulation of cell movement and leukocyte attractants

Promoting tumor cell migration, invasion and metastasis; promoting immune cell migration, maturation

Ambiguous, mainly anti-tumoral

Extracellular nonspecific chemicals

Oxygen

TME

Aerobic cellular respiration

Favor immunosuppressive phenotypes

Ambiguous

Amino acids

TME

Components and substrates for various critical processes in cell metabolism and physiology

Supporting physiological processes of both tumor and immune cells, immune regulation

Ambiguous

Glucose

TME

Major source of energy for cells

TME dependent influence of energy metabolism in both immune and tumor cells

Ambiguous

Lactate

TME

Products of glycolysis

Inhibiting anti-tumor immunity, decrease the pH within the TME

Pro-tumoral

Carbon dioxide

TME

Products of oxidative phosphorylation

Causing tumor tissue acidosis

Ambiguous

Fatty acids

TME

Involvement in biological progression and cell structure

Heterogeneous consequences for different cells, leading to immunosuppressive effects

Ambiguous

Metal ions

TME

Involvement in biological progression

Regulating tumor and immune cells

Ambiguous

  1. TME, tumor microenvironment; TIME, tumor immune microenvironment; MDSCs, myeloid-derived suppressor cells; TLSs, tertiary lymphoid structures