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PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy 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...

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Autores principales: Wang, Jun-Cheng, Chen, Dong-Ping, Lu, Shi-Xun, Chen, Jin-Bin, Wei, Yuan, Liu, Xue-Chao, Tang, Yu-Hao, Zhang, Rongxin, Chen, Jian-Cong, Kan, Anna, Xu, Li, Zhang, Yao-Jun, Hou, Jiajie, Kuang, Dong-Ming, Chen, Min-Shan, Zhou, Zhong-Guo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9478531/
https://www.ncbi.nlm.nih.gov/pubmed/35802648
http://dx.doi.org/10.1158/0008-5472.CAN-21-3899
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author Wang, Jun-Cheng
Chen, Dong-Ping
Lu, Shi-Xun
Chen, Jin-Bin
Wei, Yuan
Liu, Xue-Chao
Tang, Yu-Hao
Zhang, Rongxin
Chen, Jian-Cong
Kan, Anna
Xu, Li
Zhang, Yao-Jun
Hou, Jiajie
Kuang, Dong-Ming
Chen, Min-Shan
Zhou, Zhong-Guo
author_facet Wang, Jun-Cheng
Chen, Dong-Ping
Lu, Shi-Xun
Chen, Jin-Bin
Wei, Yuan
Liu, Xue-Chao
Tang, Yu-Hao
Zhang, Rongxin
Chen, Jian-Cong
Kan, Anna
Xu, Li
Zhang, Yao-Jun
Hou, Jiajie
Kuang, Dong-Ming
Chen, Min-Shan
Zhou, Zhong-Guo
author_sort Wang, Jun-Cheng
collection PubMed
description 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. SIGNIFICANCE: 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.
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spelling pubmed-94785312023-01-05 PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma Wang, Jun-Cheng Chen, Dong-Ping Lu, Shi-Xun Chen, Jin-Bin Wei, Yuan Liu, Xue-Chao Tang, Yu-Hao Zhang, Rongxin Chen, Jian-Cong Kan, Anna Xu, Li Zhang, Yao-Jun Hou, Jiajie Kuang, Dong-Ming Chen, Min-Shan Zhou, Zhong-Guo Cancer Res Tumor Biology and Immunology 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. SIGNIFICANCE: 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. American Association for Cancer Research 2022-09-16 2022-07-11 /pmc/articles/PMC9478531/ /pubmed/35802648 http://dx.doi.org/10.1158/0008-5472.CAN-21-3899 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Tumor Biology and Immunology
Wang, Jun-Cheng
Chen, Dong-Ping
Lu, Shi-Xun
Chen, Jin-Bin
Wei, Yuan
Liu, Xue-Chao
Tang, Yu-Hao
Zhang, Rongxin
Chen, Jian-Cong
Kan, Anna
Xu, Li
Zhang, Yao-Jun
Hou, Jiajie
Kuang, Dong-Ming
Chen, Min-Shan
Zhou, Zhong-Guo
PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma
title PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma
title_full PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma
title_fullStr PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma
title_full_unstemmed PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma
title_short PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma
title_sort pim2 expression induced by proinflammatory macrophages suppresses immunotherapy efficacy in hepatocellular carcinoma
topic Tumor Biology and Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9478531/
https://www.ncbi.nlm.nih.gov/pubmed/35802648
http://dx.doi.org/10.1158/0008-5472.CAN-21-3899
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