Cancer-Associated Fibroblasts in Inflammation and Antitumor Immunity

Abstract

Tumor-associated inflammation (TAI) is a feature of essentially all cancers and can confer both tumor-promoting and -suppressive functions. Cancer-associated fibroblasts (CAF) comprise one very heterogeneous cellular component of the tumor microenvironment characterized by a high degree of plasticity. Recent single-cell sequencing analyses revealed distinct CAF populations in various human cancers and helped to define key CAF subtypes, such as myofibroblastic, inflammatory, and antigen-presenting CAFs, with the first two being present in virtually all tumors. Importantly, these three CAF populations are involved in and modulate the positive and negative consequences of TAI. The remarkable plasticity of CAFs allows them to shift phenotypically and functionally in response to environmental changes. In this review, we describe how CAFs nurture tumor-promoting inflammation and suppress adaptive immunity. We also summarize the recently emerging evidence pertaining to tumor-suppressive CAF functions in the context of TAI. Finally, we summarize therapeutic concepts that aim at modulating CAF functions or depleting immunosuppressive CAFs to synergize with immunotherapy.

Figure 1.

CAF origins, important subtypes, and functions. Top, CAFs are derived from various cell types, the most important one being tissue-resident fibroblasts or fibroblast-like cells, including hepatic and pancreatic stellate cells. Other sources of CAFs are epithelial or endothelial cells that have undergone epithelial/endothelial-to-mesenchymal transition (EM- or EndMT) and circulating bone marrow–derived mesenchymal stem cells. Several external stimuli induce CAF activation, including TGFβ, pro-inflammatory cytokines, Notch signaling, and many more. Middle, Specific stimuli give rise to different CAF subsets. TGFβ can be considered as the key cytokine provoking a myofibroblastic (my)CAF phenotype, whereas pro-inflammatory cytokines such as IL1, IL6, and TNFα generate inflammatory (i)CAFs. The specific stimulus(i) governing formation of antigen-presenting (ap)CAFs have not been described yet, although a combination of IL1 and TGFβ has been proposed (45). Bottom, Importantly, myCAF, iCAF, and apCAFs all possess tumor-promoting and -suppressive functions by influencing the TME via different routes. PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; α-SMA, alpha smooth muscle actin; TAGLN, transgelin; PDGFRA, platelet-derived growth factor receptor alpha; MHCII, major histocompatibility complex II. (Adapted from an image created with BioRender.com.)

Figure 2.

CAF plasticity. CAF phenotypes are induced by inflammatory (IL1/IL6/TNF) or fibrotic (TGFβ) signaling. However, these phenotypes are not mutually exclusive and shift in response to environmental changes induced by tumor progression or therapeutic measures. (Adapted from an image created with BioRender.com.)

Figure 3.

CAFs as targets in cancer immunotherapy. Immunosuppressive and otherwise pro-tumorigenic CAF subsets such as FAP⁺, my-, and iCAFs can be targeted via various routes. CAF-directed therapy might be synergistic with ICB. (Adapted from an image created with BioRender.com.)