Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer
Abstract Impressive clinical benefit is seen in clinic with PD‐1 inhibitors on portion of cancer patients. Yet, there remains an urgent need to develop effective synergizers to expand their clinical application. Tumor‐associated macrophage (TAM), a type of M2‐polarized macrophage, eliminates or supp...
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114502 |
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| author | Qian Zhou Jinxia Liang Tong Yang Jin Liu Bo Li Yingchang Li Zhenzhen Fan Weida Wang Wensheng Chen Sujing Yuan Meng Xu Qigui Xu Zhidong Luan Zhongjun Xia Penghui Zhou Yadong Huang Liang Chen |
| author_facet | Qian Zhou Jinxia Liang Tong Yang Jin Liu Bo Li Yingchang Li Zhenzhen Fan Weida Wang Wensheng Chen Sujing Yuan Meng Xu Qigui Xu Zhidong Luan Zhongjun Xia Penghui Zhou Yadong Huang Liang Chen |
| author_sort | Qian Zhou |
| collection | DOAJ |
| description | Abstract Impressive clinical benefit is seen in clinic with PD‐1 inhibitors on portion of cancer patients. Yet, there remains an urgent need to develop effective synergizers to expand their clinical application. Tumor‐associated macrophage (TAM), a type of M2‐polarized macrophage, eliminates or suppresses T‐cell‐mediated anti‐tumor responses. Transforming TAMs into M1 macrophages is an attractive strategy of anti‐tumor therapy. Here, we conducted a high‐throughput screening and found that Carfilzomib potently drove M2 macrophages to express M1 cytokines, phagocytose tumor cells, and present antigens to T cells. Mechanistically, Carfilzomib elicited unfolded protein response (UPR), activated IRE1α to recruit TRAF2, and activated NF‐κB to transcribe genes encoding M1 markers in M2 macrophages. In vivo, Carfilzomib effectively rewired tumor microenvironment through reprogramming TAMs into M1‐like macrophages and shrank autochthonous lung cancers in transgenic mouse model. More importantly, Carfilzomib synergized with PD‐1 antibody to almost completely regress autochthonous lung cancers. Given the safety profiles of Carfilzomib in clinic, our work suggested a potentially immediate application of combinational treatment with Carfilzomib and PD‐1 inhibitors for patients with solid tumors. |
| format | Article |
| id | doaj-art-a5e0e58dd2f14cd383c1a32c658a93a5 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a5e0e58dd2f14cd383c1a32c658a93a52025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-12-0114112010.15252/emmm.202114502Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancerQian Zhou0Jinxia Liang1Tong Yang2Jin Liu3Bo Li4Yingchang Li5Zhenzhen Fan6Weida Wang7Wensheng Chen8Sujing Yuan9Meng Xu10Qigui Xu11Zhidong Luan12Zhongjun Xia13Penghui Zhou14Yadong Huang15Liang Chen16Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityKey Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityKey Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityKey Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityKey Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityKey Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityKey Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityState Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterKey Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan UniversityState Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterDepartment of Oncology, The First Affiliated Hospital, Jinan UniversityTranslational medicine laboratory, People’s Hospital of Yangjiang CityTranslational medicine laboratory, People’s Hospital of Yangjiang CityState Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer CenterGuangdong Province Key Laboratory of Bioengineering Medicine, Jinan UniversityDepartment of Oncology, The First Affiliated Hospital, Jinan UniversityAbstract Impressive clinical benefit is seen in clinic with PD‐1 inhibitors on portion of cancer patients. Yet, there remains an urgent need to develop effective synergizers to expand their clinical application. Tumor‐associated macrophage (TAM), a type of M2‐polarized macrophage, eliminates or suppresses T‐cell‐mediated anti‐tumor responses. Transforming TAMs into M1 macrophages is an attractive strategy of anti‐tumor therapy. Here, we conducted a high‐throughput screening and found that Carfilzomib potently drove M2 macrophages to express M1 cytokines, phagocytose tumor cells, and present antigens to T cells. Mechanistically, Carfilzomib elicited unfolded protein response (UPR), activated IRE1α to recruit TRAF2, and activated NF‐κB to transcribe genes encoding M1 markers in M2 macrophages. In vivo, Carfilzomib effectively rewired tumor microenvironment through reprogramming TAMs into M1‐like macrophages and shrank autochthonous lung cancers in transgenic mouse model. More importantly, Carfilzomib synergized with PD‐1 antibody to almost completely regress autochthonous lung cancers. Given the safety profiles of Carfilzomib in clinic, our work suggested a potentially immediate application of combinational treatment with Carfilzomib and PD‐1 inhibitors for patients with solid tumors.https://doi.org/10.15252/emmm.202114502immunotherapyM1 macrophageM2 macrophagetumor microenvironmenttumor‐associated macrophage |
| spellingShingle | Qian Zhou Jinxia Liang Tong Yang Jin Liu Bo Li Yingchang Li Zhenzhen Fan Weida Wang Wensheng Chen Sujing Yuan Meng Xu Qigui Xu Zhidong Luan Zhongjun Xia Penghui Zhou Yadong Huang Liang Chen Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer EMBO Molecular Medicine immunotherapy M1 macrophage M2 macrophage tumor microenvironment tumor‐associated macrophage |
| title | Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer |
| title_full | Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer |
| title_fullStr | Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer |
| title_full_unstemmed | Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer |
| title_short | Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer |
| title_sort | carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer |
| topic | immunotherapy M1 macrophage M2 macrophage tumor microenvironment tumor‐associated macrophage |
| url | https://doi.org/10.15252/emmm.202114502 |
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