PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma.
PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma.
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促炎巨噬细胞诱导的 PIM2 表达抑制肝细胞癌的免疫治疗效果
DOI：
10.1158/0008-5472.can-21-3899
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发表时间：
2022-09-16
期刊：
影响因子：
11.2
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中科院分区：
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T细胞和巨噬细胞之间的串扰调节癌细胞PIM 2表达以促进癌症侵袭性，揭示了改善肝细胞癌中对ICB反应的翻译方法。癌症免疫疗法恢复或增强肿瘤微环境中T细胞的效应子功能，但免疫疗法的疗效受到治疗耐药性的阻碍。在这里，我们确定了原癌基因丝氨酸/苏氨酸蛋白激酶PIM 2作为一种新的负反馈调节因子的IFNγ引起的肿瘤炎症，从而赋予癌细胞的侵略性特征。从机制上讲，来自IFNγ极化的肿瘤巨噬细胞的IL 1 β通过p38 MAPK/Erk和NF-κB信号通路触发癌细胞中PIM 2的表达。由促炎性巨噬细胞产生的PIM 2+癌细胞获得存活、转移和抵抗T细胞细胞毒性和免疫疗法的能力。一种将免疫检查点阻断（ICB）与IL 1 β阻断或PIM 2激酶抑制相结合的治疗策略在体内有效并成功地引起肿瘤消退。这些结果提供了对PIM 2+肿瘤的调节和功能特征的深入了解，并表明影响炎性细胞或PIM 2激酶的功能活性的策略可能会提高免疫治疗的疗效。T细胞和巨噬细胞之间的串扰调节癌细胞PIM 2表达以促进癌症侵袭性，揭示了改善肝细胞癌中对ICB反应的翻译方法。
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. 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.