Radiation-Induced Immunity and Toxicities: The Versatility of the cGAS-STING Pathway

Abstract

In the past decade, radiation therapy (RT) entered the era of personalized medicine, following the striking improvements in radiation delivery and treatment planning optimization, and in the understanding of the cancer response, including the immunological response. The next challenge is to identify the optimal radiation regimen(s) to induce a clinically relevant anti-tumor immunity response. Organs at risks and the tumor microenvironment (e.g. endothelial cells, macrophages and fibroblasts) often limit the radiation regimen effects due to adverse toxicities. Here, we reviewed how RT can modulate the immune response involved in the tumor control and side effects associated with inflammatory processes. Moreover, we discussed the versatile roles of tumor microenvironment components during RT, how the innate immune sensing of RT-induced genotoxicity, through the cGAS-STING pathway, might link the anti-tumor immune response, radiation-induced necrosis and radiation-induced fibrosis, and how a better understanding of the switch between favorable and deleterious events might help to define innovative approaches to increase RT benefits in patients with cancer.

Keywords: STING; bystander immunity; cGAS; inflammation; nucleic acids; radiation; radiotherapy; targeted radionuclide therapy.

Figure 1

Summary of cancer-immune cell interactions after irradiation (EBRT, external beam radiation therapy; TRT, Targeted Radionuclide Therapy) and the involvement of dsDNA,double-stranded DNA; MN, micronucleus; sEVs, small extracellular vesicles; and cGAMP, cyclic GMP–AMP in bystander immunity.

Figure 2

Senescence-associated secretory phenotype (SASP) factors can support or suppress anti-tumor immune responses. On the left, in an immunostimulatory scenario, SASP factors secreted by tumor cells and pericytes drive the recruitment of innate immune cells (macrophages, neutrophils, natural killer (NK) and NK T cells) to mediate the clearance of senescent tumor cells. On the right, in an immunosuppressive scenario, SASP factors secreted mostly by stromal cells recruit immature myeloid cells and myeloid-derived suppressor cells (MDSCs) to dampen the cytotoxic effect of NK cells and CD8+ T lymphocytes. Anti-inflammatory mediators, including IL-6 and IL-8, are also secreted by senescent stromal and tumor cells, further increasing the immunosuppressive environment. Senescent cells are represented by a gray cytoplasm, regardless of their origin. CCL, C–C motif chemokine ligand; CXCL, C–X–C motif chemokine ligand; NK natural killer; NKT, natural killer T lymphocyte.