Radiotherapy-elicited cGAMP transfer by LRRC8 VRAC promotes anticancer T cell response

Abstract In addition to conducting Cl −efflux in response to cell swelling, LRRC8 VRACs have been implicated in transporting cGAMP to the bystander cells reinforcing the IFN-I response to combat HSV-1 infection. However, a plausible role of LRRC8 VRAC-mediated cGAMP transfer in cancer immunity and autoimmunity has not been explored. Here, we demonstrate that the radiation-triggered regression of implanted tumors largely depends on the host expression of Lrrc8a, especially in the T and dendritic cell compartments. Inducibly ablating Lrrc8a expression through tamoxifen or T cell-specific depletion of Lrrc8a through CD4-Cre led to diminished CD8 T cell infiltration. Moreover, the loss of Lrrc8a also impaired the expression of granzymes and IFN-γ in the tumor-infiltrated CD8 T cells. Mechanistically, our data implicate that tumor-derived cGAMP and ATP work together to trigger STING activation and IRF3/IRF7-mediated IFN-β expression in CD8 T cells. Remarkably, T cell-derived IFN-β feeds back to empower CD8 T cell’s cytolytic capacity through the induction of a subset of ISGs. In addition to radiotherapy, our observation that LRRC8 VRAC regulates anticancer immunity also extends to chemotherapy. Together, our study supports the emerging notion that both radio- and chemotherapies have the ability to boost anticancer immunity and reveal a crucial role for LRRC8 VRAC-mediated cGAMP transport in this process. Supported by grants from National Natural Science Foundation of China.