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Table 1 Cellular components and corresponding functions within TME

From: Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

Cell type

Biomarker(s)

Functions in the TME

References

T cells

CD4+ T cells

CD4

(1) Inducing CD8+ T cell responses;

(2) Secreting interferon γ (IFNγ) and tumor necrosis factor (TNF);

(3) Releasing anti-inflammatory factors

[14]

CD8+ T cells

CD8

(1) Specific recognition of antigenic peptides-MHC class I molecular complexes;

(2) Secreting IFN-γ and the protease granzyme B;

(3) Killing cancer cells via perforin-mediated apoptosis and FASL-FAS-mediated cell death;

(4) Noncytolytic subsets have also been identified

[15, 34]

Tregs

CD25, Foxp3

(1) Secreting inhibitory cytokines;

(2) Killing effector cells by granzymes and perforin;

(3) Affecting effector cell function;

(4) Reinforcing immunosuppression

[16]

γδ T cells

CD3, γδ

(1) Recognizing antigen in an MHC-independent way;

(2) Directly recognizing cancer cells through TCR and/or natural killer cell receptors (NKRs);

(3) Indirectly displaying antitumor function via influencing downstream immune responses;

(4) Producing IL-17 to enhance tumorigenicity

[17]

B cells

CD19

(1) Following antigen presentation;

(2) Activating T cells;

(3) Recognition of tumor antigens by BCRs and direct killing of tumor cells;

(4) Generation of pro-inflammatory factors like IL-1β

(5) Inhibiting anti-cancer immunity through promotion of immune tolerance and direct suppression of T cells

[19]

Macrophages

M1

CD86, CD64, MARCO

(1) Direct cytotoxicity;

(2) Tumor cell elimination through ADCC

[20, 35]

M2

CD206, CD163, ARG1

(1) Immunosuppression;

(2) Releasing chemokines such as VEGFA, PDGF, MMPs, HIF, IL-10, COX2, and adrenomedullin to facilitate angiogenesis and lymphangiogenesis;

(3) Promoting metastasis;

(4) supporting drug resistance

[20, 36]

Dendritic cells (DCs)

CD11c, HLA-DR

(1) Presenting antigen;

(2) Inducing and maintaining CD8+ T cell responses

[37, 38]

Mast cells

CD32, CD33, CD117

(1) Promoting angiogenesis via secreting factors like IL-8, NGF, TGF-β VEGF-A, and VEGF-B;

(2) Releasing MMPs to support tumor invasion;

(3) Eliminating tumor cells through secreting IL-1, IL-4, IL-6, and TNF-α;

(4) Enhancing tumor expansion via secreting FGF-2, NGF, PDGF, VEGF, IL-8, and IL-10

[21, 39]

NK cells

CD56, NKp46, CD94

(1) Tumor cytotoxic activity;

(2) Killing cancer cells via the ‘missing-self’ mechanism;

(3) Secreting cytokines like IFN-γ and TNF-α

[22, 40]

Monocytes

CD14

(1) Differentiating into TAMs, tumor-associated DCs (TADCs), and MDSCs;

(2) Tumor cytotoxicity;

(3) Activating APCs;

(4) Potentiating angiogenesis and reshaping ECM

(5) Immunosuppression

[23, 41]

Neutrophils

CD11b, CD16

(1) Directly killing cancer cells and trogoptosis;

(2) Altering TME through improving T lymphocyte response and influencing macrophages;

(3) releasing ROS and PGE2;

(4) Immunosuppression;

(5) Promoting cancer angiogenesis

[24]

Eosinophils

CD125, Siglec-8+

(1) Tumor cell toxicity;

(2) Vessel normalization;

(3) Secreting various soluble factors such as IL-10, IL-12 and cytotoxic proteins, such as MBP and ECP;

(4) favoring tumor progression via remodeling ECM, inducing macrophage polarization, and suppressing immune response

[25]

Basophils

CD22, CD123

(1) Releasing proangiogenic factors like VEGF-A, VEGF-B, ANGPT1, and HGF;

(2) Secreting granzyme B, TNF-α, and histamine

[26, 42,43,44]

Mesenchymal stromal cells (MSCs)

CD105, CD73, CD90

(1) Promoting tumor growth and progression via secreting cytokines and chemokines like VEGF, TGF-β1, IL-6 and IL-8;

(2) Tumor toxicity and TLR expression;

(3) Exosome releasing

[27, 45, 46]

Myeloid-derived suppressor cells (MDSCs)

CD11b, Gr 1, Ly6G, Ly6C

(1) Suppressing T-cell through the high expression of ARG1, iNOS, and ROS and depletion of required amino acids;

(2) Inhibiting NK cells, DCs, and B cells;

(3) Promoting vascularization and pre-metastatic niche formation

[28, 47, 48]

Cancer-associated fibroblasts (CAFs)

FAP, α-SMA

(1) Promoting tumor growth, angiogenesis, metastasis, and drug resistance;

(2) Remodeling ECM;

(3) Suppressing immunity;

(4) Cancer-restraining function

[49, 50]

Pericytes

PDGFR-β, αSMA, CD146, NG2

(1) Modulating immunosuppressive TME;

(2) Forming the pre-metastatic niche;

(3) Participating in EMT

[29, 51]

Adipocytes

ASC-1

(1) Secreting pro-inflammatory cytokines, adiponectin, and autotaxin (ATX);

(2) Altering cancer cell metabolism

[30, 52]

  1. Abbreviations: ADCC Antibody-dependent cell-mediated cytotoxicity, ANGPT1 Angiopoietin 1, APC Antigen presenting cell, ARG1 Arginase 1, BCR B cell receptor, CD Clusters of differentiation, COX2 Cyclooxygenase 2, CXCL8 C–X–C motif chemokine ligand 8, ECM, Extracellular matrix, ECP Eosinophil cationic protein, EMT Epithelial-to-mesenchymal transition, FAP Fibroblast activation protein, FAS Factor-related apoptosis, FOXP3 Forkhead box protein P3, HGF Hepatocyte growth factor, HIF Hypoxia-inducible factor, iNOS Inducible-NO synthase, MBP Major basic protein, MMPs Matrix metalloproteinases, NGF Nerve growth factor, PDGFR-β Platelet-derived growth factor receptor β, PGE2 Prostaglandin E2, ROS Reactive oxygen species, TCR T cell receptor, TLR Toll-like receptor, VEGF-A Vascular endothelial growth factor-A, VEGF-B Vascular endothelial growth factor-B, α-SMA α-smooth muscle actin