Immunobiology of cancer-associated fibroblasts in the context of radiotherapy

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.