TGF-β Mediated Immune Evasion in Cancer—Spotlight on Cancer-Associated Fibroblasts

SIMPLE SUMMARY: The different components surrounding a tumor are collectively known as the tumor microenvironment (TME). The transforming growth factor-beta (TGF-β) signaling pathway is activated in the TME and the tumor, leading to alteration in the composition of the TME that favors tumor growth and aggressiveness. A major component of the TME, called Cancer-Associated Fibroblasts (CAFs) help the tumor grow and escape destruction by the host immune system. TGF-β signaling and CAF-associated alterations in the TME may also predict the response to cancer immunotherapy. Whether these changes in the TME are targetable alone or in combination with TGF-β inhibition is now being tested in the clinic. ABSTRACT: Various components of the tumor microenvironment (TME) play a critical role in promoting tumorigenesis, progression, and metastasis. One of the primary functions of the TME is to stimulate an immunosuppressive environment around the tumor through multiple mechanisms including the activation of the transforming growth factor-beta (TGF-β) signaling pathway. Cancer-associated fibroblasts (CAFs) are key cells in the TME that regulate the secretion of extracellular matrix (ECM) components under the influence of TGF-β. Recent reports from our group and others have described an ECM-related and CAF-associated novel gene signature that can predict resistance to immune checkpoint blockade (ICB). Importantly, studies have begun to test whether targeting some of these CAF-associated components can be used as a combinatorial approach with ICB. This perspective summarizes recent advances in our understanding of CAF and TGF-β-regulated immunosuppressive mechanisms and ways to target such signaling in cancer.