Cancer-associated fibroblasts: key determinants of tumor immunity and immunotherapy

Abstract

Immune-targeted approaches are rapidly changing the therapeutic landscape for cancer. In spite of that, most patients show resistance or acquire resistance to these therapies. Increasing work describing the tumor microenvironment (TME) has highlighted this space as one of the key determinants in tumor immune response and immunotherapeutic success. Frequently overlooked within this space, cancer-associated fibroblasts (CAFs) within the TME have surfaced as an important dictator of the tumor immune response. Herein, we review recent advances in defining the role of CAF-immune cell interactions in solid tumors and prospects for targeting stroma to overcome resistance to immunotherapy.

Tumor Microenvironment in Ovarian Cancer: Function and Therapeutic Strategy

“…Several therapies are targeting CAFs in ovarian cancer: (1) direct deletion FAP+ fibroblasts; (2) reverting the activated CAFs into a quiescent state; (3) targeting CAF-specific pathways (Chen and Song, 2019;Barrett and Puré, 2020;Truffi et al, 2020).…”

“…It is well known that CAF has phenotypic heterogeneity. Activated CAFs can selectively express a variety of different biomarkers in specific TMEs environments, such as alpha-SMA FAP, S100A4 and PDGFR (Barrett and Puré, 2020). FAP is a serine protease, which regulates the recruitment, proliferation and differentiation of myofibroblasts.…”

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“…FAP+ fibroblasts display increased ECM alignment [16] and synthesis, yet lower contractility and ECM crosslinking, while displaying higher levels of paracrine growth factors and inflammatory gene expression profiles [17]. Mechanistically, Puré highlighted a novel ECMinformed stromagenic switch -regulated by multiple factors including substratum stiffness, PDGF, TGFβ, sonic hedgehog, and osteopontin -that contributes to CAF heterogeneity and is a key component of the transition from a tumor-resistant to a tumor-permissive microenvironment [18].…”

Molecular imaging of tumor-specific markers and their expression in other organs

“…Solid cancers also require fibroblasts to provide the matrix for their growth and invasiveness. 13 Several factors secreted from cancer cells or immune cells, such as transforming growth factor beta (TGF-b), platelet derived growth factor (PDGF), hepatocyte growth factor (HGF) and fibroblast growth factor (FGF), metalloproteinases and reactive oxygen species can activate normal fibroblasts and recruit them for cancer cells. These activated and recruited fibroblasts are known as cancer-associated fibroblasts (CAF).…”

“…Several bioactive peptides and structural proteins are physiological FAP substrates. [13][14][15] FAP is expressed during embryonic development, but its expression under physiological conditions is very low in the adult tissues. However, FAP expression is high in the CAF of solid cancers and in granulation tissue of healing wounds.…”