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

Yue Wang, Dhamotharan Pattarayan, Haozhe Huang, Yueshan Zhao, Sihan Li, Yifei Wang, Min Zhang, Song Li and Da Yang ()
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Yue Wang: Department of Pharmaceutical Sciences, University of Pittsburgh
Dhamotharan Pattarayan: Department of Pharmaceutical Sciences, University of Pittsburgh
Haozhe Huang: Department of Pharmaceutical Sciences, University of Pittsburgh
Yueshan Zhao: Department of Pharmaceutical Sciences, University of Pittsburgh
Sihan Li: Department of Pharmaceutical Sciences, University of Pittsburgh
Yifei Wang: Department of Pharmaceutical Sciences, University of Pittsburgh
Min Zhang: Department of Pharmaceutical Sciences, University of Pittsburgh
Song Li: Department of Pharmaceutical Sciences, University of Pittsburgh
Da Yang: Department of Pharmaceutical Sciences, University of Pittsburgh

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Chemo-immunotherapy combinations have been regarded as one of the most practical ways to improve immunotherapy response in cancer patients. In this study, we integrate the transcriptomics data from anti-PD-1-treated tumors and compound-treated cancer cell lines to systematically screen for chemo-immunotherapy synergisms in silico. Through analyzing anti-PD-1 induced expression changes in patient tumors, we develop a shift ability score to measure if a chemotherapy or a small molecule inhibitor treatment can shift anti-PD-1 resistance in tumor cells. By applying shift ability analysis to 41,321 compounds and 16,853 shRNA treated cancer cell lines transcriptomic data, we characterize the landscape of chemo-immunotherapy synergism and experimentally validated a mitochondrial RNA-dependent mechanism for drug-induced immune activation in tumor. Our study represents an effort to mechanistically characterize chemo-immunotherapy synergism and will facilitate future pre-clinical and clinical studies.

Date: 2024
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DOI: 10.1038/s41467-024-47433-y

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