Cancer-associated fibroblasts: heterogeneity and their role in the tumor immune response

Abstract

In recent decades, many reports have been published on the composition and function of the tumor microenvironment (TME), among which cancer-associated fibroblasts (CAFs) have received much attention. CAFs have different degrees of heterogeneity in terms of their origin, phenotype, and function and can be divided into different subpopulations. These subgroups may play different roles in the occurrence and development of tumors. In addition, CAFs are closely associated with tumor immunity and have been found to regulate immune cell activity and to suppress the tumor immune response. In this review, we systematize the heterogeneity and characteristics of CAFs, discuss how specific CAF subgroups contribute to cancer progression by inducing an immunosuppressive microenvironment, and finally, we examine the future clinical applications of CAF subgroups.

Keywords: Cancer cells; Cancer-associated fibroblasts; Heterogeneity; Immunosuppression.

Fig. 1

Several origins of CAF. In tumors, normal fibroblasts, adipocytes, vascular endothelial cells, tissue-resident cells, pericytes and bone marrow-derived mesenchymal stem cells can be transformed into CAF, showing the heterogeneity of CAF origin

Fig. 2

Interaction between CAF and immune cells. CAF induces T-cell death through PD-L2 and FASL; IDO and VEGF secreted by CAF can inhibit the activity of DC; TGF-β secreted by CAF can reduce the expression of NKG2D, NKp30 and NKp44 receptors on NK cell. CAF inhibit the activity of NK cell by reducing PVR; TGF-β secreted by Tregs induces CD8+T cell apoptosis by promoting the conversion of NF to CAF. IL1R2+Tregs up regulate MHC-II expression in CAF; CAF secretes IL-6 and SDF-1α to induce the activation of MDSC. CAF with high FAP expression up regulates the secretion of CCL2 through STAT3 signal to recruit MDSC