Immunobiology of cancer-associated fibroblasts in the context of radiotherapy

Abstract

Radiotherapy (RT) still represents a mainstay of treatment in clinical oncology. Traditionally, the effectiveness of radiotherapy has been attributed to the killing potential of ionizing radiation (IR) over malignant cells, however, it has become clear that therapeutic efficacy of RT also involves activation of innate and adaptive anti-tumor immune responses. Therapeutic irradiation of the tumor microenvironment (TME) provokes profound cellular and biological reconfigurations which ultimately may influence immune recognition. As one of the major constituents of the TME, cancer-associated fibroblasts (CAFs) play central roles in cancer development at all stages and are recognized contributors of tumor immune evasion. While some studies argue that RT affects CAFs negatively through growth arrest and impaired motility, others claim that exposure of fibroblasts to RT promotes their conversion into a more activated phenotype. Nevertheless, despite the well-described immunoregulatory functions assigned to CAFs, little is known about the interplay between CAFs and immune cells in the context of RT. In this review, we go over current literature on the effects of radiation on CAFs and the influence that CAFs have on radiotherapy outcomes, and we summarize present knowledge on the transformed cellular crosstalk between CAFs and immune cells after radiation.

Keywords: CAFs; Cancer-associated fibroblasts; Immunosuppression; Ionizing radiation; Radiotherapy; TME; Tumor microenvironment.

Fig. 1

CAF-mediated immunoregulatory functions in the tumor microenvironment. Cancer-associated fibroblasts (CAFs) participate actively in the reciprocal communication with tumor and immune cells in the tumor microenvironment (TME) and are recognized contributors to immune escape by affecting recruitment and function of different innate and adaptive immune cells. Effects from CAFs on immune cells can be exerted directly via release of potent immune regulators and exosomes and/or expression of regulatory receptors on the cell surface, as well as indirectly by regulation of extracellular matrix (ECM), tissue stiffness, angiogenesis and hypoxia. Red arrows represent negative regulation, and blue arrows represent positive regulation. bFGF basic fibroblast growth factor; CD73 cluster-of-differentiation-73; CCL2 chemokine (C–C motif) ligand 2; CHI3L1 chitinase-3 like protein 1; coll collagen; CTL cytotoxic T lymphocyte; CXCL1 chemokine (C–X–C motif) ligand 1; DC dendritic cell; ECM extracellular matrix; GM-CSF granulocyte–macrophage colony-stimulating factor; HA hyaluronan; IDO Indoleamine-2,3-dioxygenase; IL interleukin; LOX lysyl oxidase; MDSCs myeloid-derived suppressor cells; MMP matrix metalloproteinases; MØ macrophages; NK cell natural killer cell; PD-L1 programmed death ligand-1; PGE2 prostaglandin E2; SDF-1 stromal-derived factor-1; TDO2 tryptophan 2,3-dioxygenase; TGFβ transforming growth factor beta; T reg regulatory T cells; TSLP thymic stromal lymphopoietin; VEGF vascular endothelial growth factor. Schematic created by BioRender

Fig. 2

Side-by-side comparison of radiation effects exerted on normal fibroblasts and cancer-associated fibroblasts (CAFs). Compared to their normal counterparts, CAFs exhibit higher proliferation and migration rates, and actively participate in sustaining a pro-inflammatory and immunosuppressive tumor microenvironment. Exposure to ionizing radiation (IR) in vitro have been shown to activate normal tissue resident fibroblasts, rendering them more pro-tumorigenic, whereas the effects of radiation on CAF tumorigenic functions remain controversial. NFs normal fibroblasts; iNFs irradiated normal fibroblasts; iCAFs irradiated CAFs

Fig. 3

Cancer-associated fibroblasts (CAFs) maintain their immunosuppressive phenotype following exposure to ionizing radiation (IR). Radiation treatment by IR is able to induce weighty changes in the phenotype of CAFs, however recent studies have demonstrated that CAFs retain their immunosuppressive functions over different innate and adaptive immune cells after radiation treatment. The release of key immunoregulators remain constant in radiation-induced senescent CAFs. In contrast to what has been observed with tumor cells, CAFs do not undergo immunogenic cell death (ICD) and do not activate interferon type 1 (IFN-1) responses following radiation, while expression of some inhibitory surface receptors is enhanced. CCL2 chemokine (C–C motif) ligand 2; CHI3L1 chitinase-3 like protein 1; CD73 cluster-of-differentiation-73; CTL cytotoxic T lymphocytes; DC dendritic cells; FasL Fas (or CD95) ligand; GM-CSF granulocyte–macrophage colony-stimulating factor; ICD immunogenic cell death; IDO Indoleamine-2,3-dioxygenase; IFN-1 type I interferon; IL-6 interleukin-6; Mø Macrophages; M2-MØs (anti-inflammatory) type-2 macrophages; NK cell natural killer cell; PD-L1 programmed death ligand-1; PGE2 prostaglandin E2; TDO2 tryptophan 2,3-dioxygenase; tDC tolerogenic dendritic cell; TSLP thymic stromal lymphopoietin; TGFb transforming growth factor beta. Schematic created by BioRender