Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer

Chemo-immunotherapy combinations have been regarded as one of the most practical ways to improve immunotherapy response in cancer patients. In this study, we integrated the transcriptomics data from immunotherapy-treated tumors and compound-treated cell lines to systematically identify chemo-immunotherapy synergisms and their underlying mechanisms. Through analyzing anti-PD-1 treatment induced expression changes in patient tumors, we developed a shift ability score that can measure whether a chemotherapy treatment shifts anti-PD-1 response. By applying the shift ability analysis on 41,321 compounds and 16,853 shRNA treated cancer cell line expression profiles, we characterized a systematic landscape of chemo-immunotherapy synergism and prioritized 17 potential synergy targets. Further investigation of the treatment induced transcriptomic data revealed that a mitophagy-dsRNA-MAVS-dependent activation of type I IFN signaling may be a novel mechanism for chemo-immunotherapy synergism. Our study represents the first comprehensive effort to mechanistically characterize chemo-immunotherapy synergism and will facilitate future pre-clinical and clinical studies.