Autophagy in tumor cells and the host STING pathway are critical for innate immune sensing of tumors and bridging to an adaptive immune response (P2183)

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Abstract Spontaneous T cell responses against tumors occur frequently. However, the mechanisms by which innate immune responses become induced in response to cancer, and how they can bridge to T cell priming against tumor antigens, have remained poorly defined. We recently reported that host type I IFN signals are required for a spontaneous T cell response against tumors. In the current work, we have mapped the sensing mechanism to one involving STING/TBK1/IRF3 which drives IFN-β transcription by host APCs. The tumor-derived ligand that triggers this pathway appears to be DNA. Using the DNA-specific dye DRAQ5 or EDU labeling, we demonstrated transfer of tumor DNA to host APCs via single cell ImageStream analysis; this was confirmed using PCR specific for tumor DNA. This was associated with IFN-β mRNA induction and nuclear translocation of IRF-3, which were dependent upon host STING. We hypothesized that autophagosome provide a mechanism for delivery of protected tumor DNA into APCs. By inhibition of tumor cell autophagy using the chemical 3-MA, or shRNA silencing of Becn or ATG5, we found marked reduction in the induction of host IFN-β production and spontaneous T cell responses in vivo. Our data suggest that tumor cell autophagy is required for optimal T cell priming against tumor antigens in vivo, that occurs through DNA-mediated activation of host IFN-β production via a STING-dependent pathway.