1IN - TREX1 as a gate-keeper of cGAS/STING-mediated activation of interferon type I in cancer cells treated with DNA-damaging agents

Abstract

Background: The presence of DNA in the cytosol during viral infection elicits virus-specific immunity, a process orchestrated by the induction of interferon type I (IFN-I), which recruits and activates dendritic cells (DCs) capable of cross-priming CD8 T cell against viral antigens. Cytosolic double-stranded (ds)DNA is sensed by the cyclic GMP-AMP synthase (cGAS), which produces cGAMP and activates the downstream adaptor stimulator of IFN genes (STING) to induce IFN-I. CD8 T cells are also key anti-tumor effectors and their activation is largely dependent on the same pathways that regulate the activation of virus-specific CD8 T cells. Endogenous DNA accumulates in the cytosol of cells that harbor defects in the DNA damage repair (DDR) machinery, a common feature of neoplastic cells that can be exploited by DNA damaging chemotherapy and ionizing radiation (IR) to mimic a viral infection and activate cGAS/STING pathway in cancer cells. Methods: Using several mouse and human carcinoma models we have tested in vitro and in vivo the IR doses and fractionation schedules that optimally induce cancer cell-intrinsic IFN-I production and synergize with immune checkpoint blockade (ICB) to elicit abscopal effects (regression of synchronous non-irradiated tumors). Results: We found that cytosolic IFN-stimulatory dsDNA accumulation is regulated by the single IR dose size, with an optimal window ranging between 4-12 Gy in most human and mouse carcinoma cells tested. Above these doses, upregulation of the DNA exonuclease TREX1 results in clearance of cytosolic dsDNA, abrogating radiation immunogenicity. Fractionation, i.e., repeated (3 times) daily delivery of radiation therapy at doses within this window, amplifies the IFN-I pathway activation, an effect that requires induction of IFNRA. Using genetic tools we demonstrated that IR synergy with ICBs in inducing abscopal effects is completely dependent on the IR induction of cancer cell-intrinsic IFN-I (Vanpouille-Box et al., Nat Commun 2017). Conclusions: DNA damaging therapy can be used to enhance tumor immunogenicity and overcome resistance to ICBs. Improved understanding of the mechanisms that control IFN-inducing dsDNA by the TREX1 and cGAS/STING axis will lead to more effective combinations treatments for cancer. Legal entity responsible for the study: N/A Funding: National Cancer Institute (NCI), USA, R01CA201246. Disclosure: The author has declared no conflicts of interest.