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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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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. |
format | Online Article Text |
id | pubmed-9478531 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
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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