期刊
CANCER RESEARCH
卷 82, 期 18, 页码 3307-3320出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-3899
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资金
- National Natural Science Foundation of China [81874070, 81902493, 82002528, 82025016]
- Sun Yat-sen University Cancer Center [16zxqk04]
- Wu Jieping Medical Foundation special fund for tumor immunity [320.6705.2021-02-76]
- National Key R&D Program of China [2020YFE0202200]
- National Science and Technology Major Project of China [2018ZX10302205, 2018ZX10723204]
- Natural Science Foundation of Guangdong Province, China [2020A1515010895]
The proto-oncogene serine/threonine protein kinase PIM2 acts as a negative regulator of tumor inflammation, hindering the efficacy of cancer immunotherapy. IL1(3 derived from tumor macrophages triggers PIM2 expression in cancer cells, leading to their aggressive features. Inhibiting IL1(3 or PIM2 kinase combined with immune checkpoint blockade effectively induces tumor regression.
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/threo-nine protein kinase PIM2 as a novel negative feedback regulator of IFNy-elicited tumor inflammation, thus endowing cancer cells with aggressive features. Mechanistically, IL1(3 derived from IFNy-polarized tumor macrophages triggered PIM2 expression in cancer cells via the p38 MAPK/Erk and NF-xB signaling pathways. PIM2 thorn 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 IL1(3 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 thorn tumors and suggest that strategies to influence the functional activities of inflammatory cells or PIM2 kinase may improve the efficacy of immunotherapy.Significance: Cross-talk between T cells and macrophages reg-ulates cancer cell PIM2 expression to promote cancer aggres-siveness, revealing translational approaches to improve response to ICB in hepatocellular carcinoma.
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