Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy

Abstract

Tumor-associated fibrosis is characterized by unchecked pro-fibrotic and pro-inflammatory signaling. The components of fibrosis including significant numbers of cancer-associated fibroblasts, dense collagen deposition, and extracellular matrix stiffness, are well appreciated regulators of tumor progression but may also be critical regulators of immune surveillance. While this suggests that the efficacy of immunotherapy may be limited in highly fibrotic cancers like pancreas, it also suggests a therapeutic opportunity to target fibrosis in these tumor types to reawaken anti-tumor immunity. This review discusses the mechanisms by which fibrosis might subvert tumor immunity and how to overcome these mechanisms.

Keywords: Extracellular matrix; Fibrosis; Pancreas cancer; Regulatory myeloid suppressor cells; Tumor immunity; Tumor microenvironment.

Fig. 1

Fibrosis in cancer. Representative trichrome (blue) staining for collagen in normal pancreas and different cancerous tissues. Magnification ×20

Fig. 2

The impact of CAFs on immune cell regulation and function. CAF subsets can impair CD8⁺ CTL activation, cytokine production, and cytotoxicity; CAFs also affect CD4⁺ T cells to favor tumor-promoting T_H2 and T_H17 responses through production of chemoattractants and polarizing cytokines. Likewise, CAFs can induce suppressive T_reg differentiation and recruitment. CAFs can limit maturation of myeloid derived suppressors (MDSCs), putatively suppress M1-like macrophage activity, and/or switch monocyte differentiation programs towards a tumor-promoting M2 macrophage lineage. Also, CAFs can influence maturation and activity of DCs in the tumor microenvironment (TuDCs) to undermine CD8 T cell activation and function

Fig. 3

The impact of ECM on immune cell function. The dense collagen-rich ECM of fibrotic tumors can act as a physical barrier to CTL infiltration into tumors. Increased ECM stiffness and aligned structural barriers in a fibrotic tumor also influence the localization and migration of T cells into the tumor stroma. Tumor-associated ECM components as well as sequestered chemokine factors can influence macrophage polarization (towards an M2 signature) and affect the maturation and migration of monocytes and MDSCs. Dense ECM architecture can also prompt changes in availability of oxygen and micronutrients, inducing hypoxia and thereby influencing the immune contexture of the tumor microenvironment