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 (CAFs) comprise one very heterogenous cellular component of the tumor microenvironment (TME) 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 CAF 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.

Normal Uterine Fibroblast Are Reprogramed into Ovarian Cancer-Associated Fibroblasts by Ovarian Tumor-derived Conditioned Media

“…The immunomodulatory role of the conditioned CAFs was confirmed by the upregulation of pro-inflammatory genes and downregulation of anti-inflammatory genes (Figure 4). This coincides with previous research highlighting CAFs role in tumor-promoting inflammation 11,81 . Of note, the anti-mullerian hormone (AMH) gene is also upregulated by the conditioned CAFs, which has been recently linked to the modulation of cancer-associated mesothelial cells 47 .…”

“…An example of this is CAFs ability to induce EMT through the upregulation of transforming growth factor beta (TGF-β) 9 . CAFs are inflammatory and are mainly known to be pro-tumorigenic, largely attributed to their production of cytokines like interleukin-6 (IL-6) and CCchemokine ligand 2 (CCL2/MCP-1) that interfere with T cell function [10][11][12] . Thus, CAFs are considered to be notable players in promoting many aspects of tumor function and a promising targeted therapeutic option.…”

Characterization and Clinical Relevance of Endometrial CAFs: Correlation between Post-Surgery Event and Resistance to Drugs

“…CAFs, the most abundant and influential cells of TME, have a significant contextual role in this progression by means of resisting the therapy and ensuing metastasis reported in colon, pancreas, breast, esophagus, and skin cancers. Understanding CAFs’ undeniable role in the resistance to therapy and the progression of solid tumors has recently encouraged CAF-directed clinical trials as part of a next-generation cancer drug design and discovery innovation strategy [ 6 , 7 , 8 , 9 ].…”

Identification of a cancer-associated fibroblast classifier for predicting prognosis and therapeutic response in lung squamous cell carcinoma

“…[10] Cancer-associated fibroblasts (CAFs) constitute a significant portion of the tumor stroma in LUSC and play a critical role in the development and progression of this disease by modulating the tumor microenvironment (TME). [11,12] CAFs exhibit a diverse range of functions, including recruitment of immunosuppressive cells (such as myeloid-derived suppressor cells [13] and regulatory T cells [14] ) and inhibition of the activity of effector immune cells (such as cytotoxic T cells and natural killer cells). [15,16] Additionally, CAFs secrete various cytokines and growth factors that enhance tumor cell proliferation, angiogenesis, and invasion.…”