journal contribution
posted on 2023-03-31, 05:22 authored by Jun-Cheng Wang, Dong-Ping Chen, Shi-Xun Lu, Jin-Bin Chen, Yuan Wei, Xue-Chao Liu, Yu-Hao Tang, Rongxin Zhang, Jian-Cong Chen, Anna Kan, Li Xu, Yao-Jun Zhang, Jiajie Hou, Dong-Ming Kuang, Min-Shan Chen, Zhong-Guo Zhou Supplementary Data from PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma
Funding
National Natural Science Foundation of China
Sun Yat-sen University Cancer Center physician scientist
Wu Jieping Medical Foundation special
National Key R&D Program of China
National Science and Technology Major Project of China
History
ARTICLE ABSTRACT
Cancer immunotherapy restores or enhances the effector function of T cells in the tumor microenvironment, but the efficacy of immunotherapy has been hindered by therapeutic resistance. Here, we identify the proto-oncogene serine/threonine protein kinase PIM2 as a novel negative feedback regulator of IFNγ-elicited tumor inflammation, thus endowing cancer cells with aggressive features. Mechanistically, IL1β derived from IFNγ-polarized tumor macrophages triggered PIM2 expression in cancer cells via the p38 MAPK/Erk and NF-κB signaling pathways. PIM2+ cancer cells generated by proinflammatory macrophages acquired the capability to survive, metastasize, and resist T-cell cytotoxicity and immunotherapy. A therapeutic strategy combining immune checkpoint blockade (ICB) with IL1β blockade or PIM2 kinase inhibition in vivo effectively and successfully elicited tumor regression. These results provide insight into the regulatory and functional features of PIM2+ tumors and suggest that strategies to influence the functional activities of inflammatory cells or PIM2 kinase may improve the efficacy of immunotherapy.
Cross-talk between T cells and macrophages regulates cancer cell PIM2 expression to promote cancer aggressiveness, revealing translational approaches to improve response to ICB in hepatocellular carcinoma.
