Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives

Abstract

Cancer-associated fibroblasts (CAFs), a stromal cell population with cell-of-origin, phenotypic and functional heterogeneity, are the most essential components of the tumor microenvironment (TME). Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion and metastasis, along with extracellular matrix (ECM) remodeling and even chemoresistance. Numerous previous studies have confirmed the critical role of the interaction between CAFs and tumor cells in tumorigenesis and development. However, recently, the mutual effects of CAFs and the tumor immune microenvironment (TIME) have been identified as another key factor in promoting tumor progression. The TIME mainly consists of distinct immune cell populations in tumor islets and is highly associated with the antitumor immunological state in the TME. CAFs interact with tumor-infiltrating immune cells as well as other immune components within the TIME via the secretion of various cytokines, growth factors, chemokines, exosomes and other effector molecules, consequently shaping an immunosuppressive TME that enables cancer cells to evade surveillance of the immune system. In-depth studies of CAFs and immune microenvironment interactions, particularly the complicated mechanisms connecting CAFs with immune cells, might provide novel strategies for subsequent targeted immunotherapies. Herein, we shed light on recent advances regarding the direct and indirect crosstalk between CAFs and infiltrating immune cells and further summarize the possible immunoinhibitory mechanisms induced by CAFs in the TME. In addition, we present current related CAF-targeting immunotherapies and briefly describe some future perspectives on CAF research in the end.

Epigallocatechin‑3‑gallate hinders metabolic coupling to suppress colorectal cancer malignancy through targeting aerobic glycolysis in cancer‑associated fibroblasts

“…High amounts of lactic acid secreted by CAFs with an upregulated expression of MCT4 as an energy substrate are absorbed by cancer cells, and these participate in the metabolic alteration of cancer cells, thereby enhancing tumor malignancy. In the present study, the western blotting results showed that the expression levels of α-SMA and FAP, the two most widely used markers for identifying CAFs ( 41 , 42 ), were upregulated in HIFs after co-culture. Moreover, the results from the immunofluorescence staining experiments confirmed the upregulation of α-SMA and FAP, and a narrower, longer and spindle-shaped morphology of the cells was observed in the induced CAFs that was similar to that commonly exhibited in activated fibroblasts, as one of their characteristic features in CAFs ( 43 ).…”

Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring

“…They can also be used as a tool for intercellular material and information exchange and as a carrier for intercellular information transmission to transfer information molecules such as DNA, noncoding RNA (including miRNA and long-chain noncoding RNA (lncRNA)), mRNA, and protein. Exosomes are self-regulating, and can also regulate adjacent cells and distant target cells by autocrine or paracrine mechanisms, and mediate the physiological and/or pathological activities of the body [ 42 ]. Exosomes are involved in angiogenesis, EMT, invasion and metastasis, immune escape, drug resistance, and other aspects in the occurrence and development of tumors and have excellent clinical application prospects (Fig.…”

An HGF-dependent positive feedback loop between bladder cancer cells and fibroblasts mediates lymphangiogenesis and lymphatic metastasis

“…The precise interaction pro le between tumor cells and CAFs are under intensive exploration, where the extracellular vesicles (EVs) serving as crucial cargo carriers of diverse pro-tumor molecules to mediate intercellular communication have received close attention 17,18 . Tumor cell-derived EVs speci cally modify the stromal cellular phenotype and reshape the TME to form a premetastatic niche and support tumor metastasis 19 .…”