Amplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma

Abstract Background Immune checkpoint blockade resistance narrows the efficacy of cancer immunotherapies, but the underlying mechanism remains elusive. Delineating the inherent mechanisms of anti-PD1 resistance is important to improve outcome of patients with advanced HCC. Method The level of cricTM...

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Autores principales:	Jia-Cheng Lu, Peng-Fei Zhang, Xiao-Yong Huang, Xiao-Jun Guo, Chao Gao, Hai-Ying Zeng, Yi-Min Zheng, Si-Wei Wang, Jia-Bin Cai, Qi-Man Sun, Ying-Hong Shi, Jian Zhou, Ai-Wu Ke, Guo-Ming Shi, Jia Fan
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Hepatocellular carcinoma Exosomal circRNA Macrophage CD39 ATP–adenosine pathway Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/3a9346748130408cbfa3d2dff395848d
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spelling	oai:doaj.org-article:3a9346748130408cbfa3d2dff395848d2021-11-28T12:03:24ZAmplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma10.1186/s13045-021-01207-x1756-8722https://doaj.org/article/3a9346748130408cbfa3d2dff395848d2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13045-021-01207-xhttps://doaj.org/toc/1756-8722Abstract Background Immune checkpoint blockade resistance narrows the efficacy of cancer immunotherapies, but the underlying mechanism remains elusive. Delineating the inherent mechanisms of anti-PD1 resistance is important to improve outcome of patients with advanced HCC. Method The level of cricTMEM181 was measured in HCC patients with anti-PD1 therapy by RNA sequencing and then confirmed by qPCR and Sanger sequencing. Immune status in tumor microenvironment of HCC patients or mice models was evaluated by flow cytometry and IHC. Exosomes from HCC cell lines were isolated by ultracentrifugation, and their internalization by macrophage was confirmed by immunofluorescence. The underlying mechanism of HCC-derived exosomal circTMEM181 to macrophage was confirmed by SILAC, RNA FISH and RNA immunoprecipitation. The ATP–ADO pathway amplified by HCC–macrophage interaction was evaluated through ATP, AMP and ADO measurement and macrophage-specific CD39 knockout mice. The role of circTMEM181 in anti-PD1 therapy and its clinical significance were also determined in our retrospective HCC cohorts. Results Here, we found that circTMEM181 was elevated in hepatocellular carcinoma (HCC) patients responding poorly to anti-PD1 therapy and in HCC patients with a poor prognosis after operation. Moreover, we also found that high exosomal circTMEM181 favored the immunosuppressive microenvironment and endowed anti-PD1 resistance in HCC. Mechanistically, exosomal circTMEM181 sponged miR-488-3p and upregulated CD39 expression in macrophages. Using macrophage-specific CD39 knockout mice and pharmacologic approaches, we revealed a novel mode of anti-PD1 resistance in HCC. We discovered that cell-specific CD39 expression in macrophages and CD73 expression in HCC cells synergistically activated the eATP–adenosine pathway and produced more adenosine, thereby impairing CD8+ T cell function and driving anti-PD1 resistance. Conclusion In summary, HCC-derived exosomal circTMEM181 contributes to immunosuppression and anti-PD1 resistance by elevating CD39 expression, and inhibiting the ATP–adenosine pathway by targeting CD39 on macrophages can rescue anti-PD1 therapy resistance in HCC. Graphical AbstractJia-Cheng LuPeng-Fei ZhangXiao-Yong HuangXiao-Jun GuoChao GaoHai-Ying ZengYi-Min ZhengSi-Wei WangJia-Bin CaiQi-Man SunYing-Hong ShiJian ZhouAi-Wu KeGuo-Ming ShiJia FanBMCarticleHepatocellular carcinomaExosomal circRNAMacrophageCD39ATP–adenosine pathwayDiseases of the blood and blood-forming organsRC633-647.5Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-20 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Hepatocellular carcinoma Exosomal circRNA Macrophage CD39 ATP–adenosine pathway Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Hepatocellular carcinoma Exosomal circRNA Macrophage CD39 ATP–adenosine pathway Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Jia-Cheng Lu Peng-Fei Zhang Xiao-Yong Huang Xiao-Jun Guo Chao Gao Hai-Ying Zeng Yi-Min Zheng Si-Wei Wang Jia-Bin Cai Qi-Man Sun Ying-Hong Shi Jian Zhou Ai-Wu Ke Guo-Ming Shi Jia Fan Amplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma
description	Abstract Background Immune checkpoint blockade resistance narrows the efficacy of cancer immunotherapies, but the underlying mechanism remains elusive. Delineating the inherent mechanisms of anti-PD1 resistance is important to improve outcome of patients with advanced HCC. Method The level of cricTMEM181 was measured in HCC patients with anti-PD1 therapy by RNA sequencing and then confirmed by qPCR and Sanger sequencing. Immune status in tumor microenvironment of HCC patients or mice models was evaluated by flow cytometry and IHC. Exosomes from HCC cell lines were isolated by ultracentrifugation, and their internalization by macrophage was confirmed by immunofluorescence. The underlying mechanism of HCC-derived exosomal circTMEM181 to macrophage was confirmed by SILAC, RNA FISH and RNA immunoprecipitation. The ATP–ADO pathway amplified by HCC–macrophage interaction was evaluated through ATP, AMP and ADO measurement and macrophage-specific CD39 knockout mice. The role of circTMEM181 in anti-PD1 therapy and its clinical significance were also determined in our retrospective HCC cohorts. Results Here, we found that circTMEM181 was elevated in hepatocellular carcinoma (HCC) patients responding poorly to anti-PD1 therapy and in HCC patients with a poor prognosis after operation. Moreover, we also found that high exosomal circTMEM181 favored the immunosuppressive microenvironment and endowed anti-PD1 resistance in HCC. Mechanistically, exosomal circTMEM181 sponged miR-488-3p and upregulated CD39 expression in macrophages. Using macrophage-specific CD39 knockout mice and pharmacologic approaches, we revealed a novel mode of anti-PD1 resistance in HCC. We discovered that cell-specific CD39 expression in macrophages and CD73 expression in HCC cells synergistically activated the eATP–adenosine pathway and produced more adenosine, thereby impairing CD8+ T cell function and driving anti-PD1 resistance. Conclusion In summary, HCC-derived exosomal circTMEM181 contributes to immunosuppression and anti-PD1 resistance by elevating CD39 expression, and inhibiting the ATP–adenosine pathway by targeting CD39 on macrophages can rescue anti-PD1 therapy resistance in HCC. Graphical Abstract
format	article
author	Jia-Cheng Lu Peng-Fei Zhang Xiao-Yong Huang Xiao-Jun Guo Chao Gao Hai-Ying Zeng Yi-Min Zheng Si-Wei Wang Jia-Bin Cai Qi-Man Sun Ying-Hong Shi Jian Zhou Ai-Wu Ke Guo-Ming Shi Jia Fan
author_facet	Jia-Cheng Lu Peng-Fei Zhang Xiao-Yong Huang Xiao-Jun Guo Chao Gao Hai-Ying Zeng Yi-Min Zheng Si-Wei Wang Jia-Bin Cai Qi-Man Sun Ying-Hong Shi Jian Zhou Ai-Wu Ke Guo-Ming Shi Jia Fan
author_sort	Jia-Cheng Lu
title	Amplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma
title_short	Amplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma
title_full	Amplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma
title_fullStr	Amplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma
title_full_unstemmed	Amplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma
title_sort	amplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-pd1 resistance in hepatocellular carcinoma
publisher	BMC
publishDate	2021
url	https://doaj.org/article/3a9346748130408cbfa3d2dff395848d
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Amplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma

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