From gatekeepers to providers: regulation of immune functions by cancer-associated fibroblasts

Abstract

Cancer-associated fibroblasts (CAFs) are major protumorigenic components of the tumor microenvironment in solid cancers. CAFs are heterogeneous, consisting of multiple subsets that display diverse functions. Recently, CAFs have emerged as major promoters of immune evasion. CAFs favor T cell exclusion and exhaustion, promote recruitment of myeloid-derived suppressor cells, and induce protumoral phenotypic shifts in macrophages and neutrophils. With the growing appreciation of CAF heterogeneity came the understanding that different CAF subpopulations may be driving distinct immune-regulatory effects, interacting with different cell types, and perhaps even driving opposing effects on malignancy. In this review we discuss the current understanding of CAF-immune interactions, their effect on tumor progression and therapeutic response, and the possibility of exploiting CAF-immune interactions as potential targets for cancer therapy.

Keywords: CAF heterogeneity; MHC class II; T cells; TAM; apCAF; cancer; cancer-associated fibroblasts; iCAF; immune evasion; immunotherapy; macrophages; myCAF; stroma; tumor microenvironment; tumor-associated macrophages.