Mechanisms of radiation-induced tumor immunogenicity
Most cancer cells exposed to ionizing radiation do not undergo immediate death even when the damage is lethal but remain within the tumour mass for some time during which they generate molecular signals that modify the cross-talk of the tumour with the host immune system. Central to this process is the activation of the DNA damage repair (DDR) response, which is often dysregulated in neoplastic cells, and associated with DNA displacement to the cytosol. The presence of dsDNA in the cytosol is sensed by the cyclic GMP-AMP synthase, cGAS, which catalyzes the formation of the second messenger cGAMP and activates STING, leading to the production of type I interferon (IFN-I). IFN-I is a critical effector of cell-mediated anti-viral and anti-tumour immunity and is primarily responsible for the recruitment and activation of BATF3-dendritic cells (DCs), and downstream activation of anti-tumour CD8 T cells. Accumulation of cytosolic IFN-stimulatory dsDNA is regulated by the single radiation 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 (three times) daily delivery of radiation therapy at doses within this window, amplifies the IFN-I pathway activation in the carcinoma cells, an effect that requires induction of IFNRA. Furthermore, the synergy of RT with immune checkpoint blockers (ICBs) anti-CTLA-4 or anti-PD-1 and the induction of abscopal effects (i.e., immune-mediated rejection of non-irradiated synchronous tumours) are completely dependent on the ability of radiotherapy to induce cancer cell-intrinsic IFN-I. These findings have critical implications for the use of radiotherapy to increase the response to ICBs, a combination currently being tested in many clinical trials.
Supported by NIH 1R01CA201246 and R01CA198533, Breast Cancer Research Foundation, and The Chemotherapy Foundation.
Department of Radiation Oncology and Pathology and laboratory medicine, Weill Cornell Medicine, New York, NY.
Domain 1 - UMR 3347 / U1021 - Normal and pathological signaling