Abstract
Cancer-associated fibroblasts (CAFs) are important, highly heterogeneous components of the tumor extracellular matrix that have different origins and express a diverse set of biomarkers. Different subtypes of CAFs participate in the immune regulation of the tumor microenvironment (TME). In addition to their role in supporting stromal cells, CAFs have multiple immunosuppressive functions, via membrane and secretory patterns, against anti-tumor immunity. The inhibition of CAFs function and anti-TME therapy targeting CAFs provides new adjuvant means for immunotherapy. In this review, we outline the emerging understanding of CAFs with a particular emphasis on their origin and heterogeneity, different mechanisms of their regulation, as well as their direct or indirect effect on immune cells that leads to immunosuppression.
Highlights
The tumor microenvironment (TME) plays critical roles in tumor initiation, proliferation, and metastasis, and consists of cellular and extracellular matrix (ECM)
It could be suggested that cancer-associated fibroblast (CAF) heterogeneity may be partially explained by the fact that fibroblasts within one tumor can originate from different cellular precursors and from distinct cellular locations [6]
The lack of congruency in the marker expression raises the possibility that CAFs comprise a diverse group of cells made up of several subsets [32]. Support for this notion comes from recent studies on a variety of cancers, such as pancreatic ductal adenocarcinoma (PDAC), breast cancer, colon carcinoma [33], oral carcinoma [34] and lung cancer [35], in which functionally distinct subclasses of CAFs were identified by various means based on the expression of a limited set of markers [20]
Summary
The tumor microenvironment (TME) plays critical roles in tumor initiation, proliferation, and metastasis, and consists of cellular and extracellular matrix (ECM). Multiple cell types comprise the cellular compartment of the TME, including tumor cells, immune cells, endothelial cells, and cancer-associated fibroblasts (CAFs) [1]. CAFs are activated in the tumor stroma, and formulate a highly heterogeneous group of cells with rich morphological characteristics and biological functions, which contributes to tumorigenesis by secreting growth factors, modifying the ECM, supporting angiogenesis, and suppressing anti-tumor immune responses [2,3,4]. We summarize the various mechanisms concerning the immunosuppressive capabilities of activated fibroblasts in the TME, as well as their potential application for therapeutic intervention, especially in the field of tumor immunotherapy [5]
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