Different syngeneic tumors show distinctive intrinsic tumor-immunity and mechanisms of actions (MOA) of anti-PD-1 treatment

作者：Ying Jin, Xiaoyu An, Binchen Mao, Ruilin Sun, Rajendra Kumari, Xiaobo Chen, Yongli Shan, Mingfa Zang, Ling Xu, Jan Muntel, Kristina Beeler, Roland Bruderer, Lukas Reiter, Sheng Guo, Demin Zhou, Qi‐Xiang Li, Xuesong Ouyang · 发表于：Scientific Reports · 年份：2022 · DOI：10.1038/s41598-022-07153-z · 被引用次数：73 · 研究领域：Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research、Immunotherapy and Immune Responses

Abstract Cancers are immunologically heterogeneous. A range of immunotherapies target abnormal tumor immunity via different mechanisms of actions (MOAs), particularly various tumor-infiltrate leukocytes (TILs). We modeled loss of function (LOF) in four common anti-PD-1 antibody-responsive syngeneic tumors, MC38, Hepa1-6, CT-26 and EMT-6, by systematical depleting a series of TIL lineages to explore the mechanisms of tumor immunity and treatment. CD8 + -T-cells, CD4 + -T-cells, T reg , NK cells and macrophages were individually depleted through either direct administration of anti-marker antibodies/reagents or using DTR (diphtheria toxin receptor) knock-in mice, for some syngeneic tumors, where specific subsets were depleted following diphtheria toxin (DT) administration. These LOF experiments revealed distinctive intrinsic tumor immunity and thus different MOAs in their responses to anti-PD-1 antibody among different syngeneic tumors. Specifically, the intrinsic tumor immunity and the associated anti-PD-1 MOA were predominately driven by CD8 + cytotoxic TILs (CTL) in all syngeneic tumors, excluding Hepa1-6 where CD4 + T eff TILs played a key role. TIL-T reg also played a critical role in supporting tumor growth in all four syngeneic models as well as M 2 -macrophages. Pathway analysis using pharmacodynamic readouts of immuno-genomics and proteomics on MC38 and Hepa1-6 also revealed defined, but distinctive, immune pathways of activation and suppression between the two, closel...