Cancer-Associated Fibroblasts: Accomplices in the Tumor Immune Evasion

Abstract

Cancer-associated fibroblasts (CAFs) are prominent cells within the tumor microenvironment, by communicating with other cells within the tumor and by secreting the extracellular matrix components. The discovery of the immunogenic role of CAFs has made their study particularly attractive due to the potential applications in the field of cancer immunotherapy. Indeed, CAFs are highly involved in tumor immune evasion by physically impeding the immune system and interacting with both myeloid and lymphoid cells. However, CAFs do not represent a single cell entity but are divided into several subtypes with different functions that may be antagonistic. Considering that CAFs are orchestrators of the tumor microenvironment and modulate immune cells, targeting their functions may be a promising strategy. In this review, we provide an overview of (i) the mechanisms involved in immune regulation by CAFs and (ii) the therapeutic applications of CAFs modulation to improve the antitumor immune response and the efficacy of immunotherapy.

Keywords: cancer-associated fibroblasts; cell communication; immunology; tumor microenvironment.

Figure 1

Therapeutic strategies modulating CAF activities. CAF-related drugs, with or without ICI combination, inhibit fibrosis (a), CAF-protumoral subsets (b) or CAF-secreted immunosuppressive molecules (c). Abbreviations: CAF: cancer-associated fibroblasts, CCL2: chemokine-ligand 2, CCR2: C-C chemokine receptor type 2, CXCL12: C-X-C motif chemokine 12, CXCR4: C-X-C motif chemokine receptor 4, ECM: extracellular matrix, FAK: focal adhesion kinase, FAP: fibroblast activation protein, ICI: immune checkpoint inhibitors, IDO1: indoleamine 2,3-dioxygenase 1, MDSC: myeloid-derived suppressor cells, PDGFRα: platelet-derived growth factor receptor α, TAM: tumor-associated macrophage, TGFβ: transforming growth factor β, Treg: regulatory lymphocyte.