Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy

Abstract

Among all the stromal cells that present in the tumor microenvironment, cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor mesenchyme, which not only provide physical support for tumor cells but also play a key role in promoting and retarding tumorigenesis in a context-dependent manner. CAFs have also been involved in the modulation of many components of the immune system, and recent studies have revealed their roles in immune evasion and poor responses to cancer immunotherapy. In this review, we describe our current understanding of the tumorigenic significance, origin, and heterogeneity of CAFs, as well as the roles of different CAFs subtypes in distinct immune cell types. More importantly, we highlight potential therapeutic strategies that target CAFs to unleash the immune system against the tumor.

Keywords: Cancer immunotherapy; Cancer-associated fibroblasts; Heterogeneity; Immune suppression.

Fig. 1

The tumorigenic significance of CAFs in PAAD. a The expression of CAF markers (ACTA2, FAP, PDGFRα, and PDGFRβ) was markedly overexpressed in pancreatic adenocarcinoma (PAAD) tissues compared with the paired normal tissues based on TCGA database. b, c The expression of ACTA2, FAP, and PDGFRα/β positively correlated with each other significantly. d Differential expression levels of ACTA2, FAP, PDGFRα and PDGFRβ among different KRAS status

Fig. 2

Potential cellular sources of CAFs. Cancer-associated fibroblasts (CAFs) can originate from diverse cell populations. Sources of CAFs include pre-existing resident fibroblasts and stellate cells (which become CAFs through activation), epithelial cells (via epithelial-to-mesenchymal transition, EMT), endothelial cells (via endothelial-to-mesenchymal transition, EndMT), mesenchymal stem cells (MSCs), and circulating fibrocytes (via recruitment), as well as pericytes, smooth muscle cells, and adipocytes (through transdifferentiation). ECM extracellular matrix; α-SMA α-smooth muscle actin; S100A4 fibroblast specific protein-1, also called FSP-1

Fig. 3

Immunosuppressive functions of different CAFs subtypes. Cancer-associated fibroblasts (CAFs) orchestrate an immunosuppressive tumor microenvironment. Different CAFs subtypes secrete numerous chemokines and cytokines, such as transforming growth factor-β (TGF-β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-13 (IL-13), CX-chemokine ligand 12 (CXCL12), CX-chemokine ligand 14 (CXCL14), and vascular endothelial growth factor A (VEGF), thereby inhibiting both the innate and adaptive anti-tumor immune response. Of note, some subpopulations express programmed cell death 1 ligand 1/2 (PD-L1/2), a target for immune checkpoint inhibitor. Metabolites or metabolic enzymes, such as indoleamine-2,3-dioxygenase (IDO), arginase (Arg), adenosine, and tryoptase produced by certain subtypes of CAFs favor the recruitment and differentiation of regulatory T cell (Tregs), mast cells, and tumor-associated macrophages (TAMs). Finally, CAFs can synthesize the extracellular matrix (ECM) components such as collagen, fibronectin, and matrix metalloproteinases (MMPs). Multiple CAF subtypes contribute to increased ECM stiffness, which in turn reduces the infiltration of effector T cells. MDSC myeloid-derived suppressor cell, DC dendritic cell, NK natural killer cells, T_H cells CD4⁺ helper lymphocytes, N neutrophils, FAP fibroblast activation protein, PDPN podoplanin, CCL2 chemokine ligand 2, M-CSF macrophage colony-stimulating factor, PDGFR platelet-derived growth factor, APC antigen-processing cell, FASL FAS ligand

Fig. 4

Immunotherapies that target CAFs. Four general approaches that target cancer-associated fibroblasts (CAFs) for cancer immunotherapy. ① Fibroblast activation protein⁺ (FAP⁺) CAFs can be directly eliminated by transgenic technologies, immunotherapies, and oncolytic adenovirus. ② Targeting the important signals and effectors of CAFs, such as CX-chemokine ligand 12-CX chemokine receptor 4 (CXCL12-CXCR4) interaction, Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) pathway, transforming growth factor-β (TGF-β), and Hedgehog signaling pathway, can be used to inhibit the function of CAFs. ③ A reprogramming strategy such as vitamin A and vitamin D can be adopted to dedifferentiate activated CAFs to resident (normalized) fibroblasts. ④ CAF-derived extracellular matrix (ECM) proteins and associated signaling pathway can be targeted to induce stromal depletion. CAR chimeric antigen receptor, mAb monoclonal antibody, MDSC myeloid-derived suppressor cell, TAM tumor-associated macrophage, Treg cell regulatory T cell