Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer

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‐...

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Published inEMBO molecular medicine Vol. 14; no. 1; pp. e14502 - n/a
Main Authors Zhou, Qian, Liang, Jinxia, Yang, Tong, Liu, Jin, Li, Bo, Li, Yingchang, Fan, Zhenzhen, Wang, Weida, Chen, Wensheng, Yuan, Sujing, Xu, Meng, Xu, Qigui, Luan, Zhidong, Xia, Zhongjun, Zhou, Penghui, Huang, Yadong, Chen, Liang
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 11.01.2022
EMBO Press
John Wiley and Sons Inc
Springer Nature
Subjects
Animals
Antibodies
Antigen (tumor-associated)
Bone marrow
Cancer therapies
Cellular Reprogramming
Cytokines
Drug dosages
EMBO03
EMBO19
Endoribonucleases
Experiments
FDA approval
Humans
Immune checkpoint
Immune Checkpoint Inhibitors - pharmacology
Immune system
immunotherapy
Inhibitor drugs
Kinases
Ligands
Lung cancer
Lung Neoplasms - drug therapy
Lymphocytes
Lymphocytes T
M1 macrophage
M2 macrophage
Macrophages
Mice
Mice, Transgenic
Multiple myeloma
Oligopeptides - pharmacology
Patients
Protein folding
Protein Serine-Threonine Kinases
Proteins
Solid tumors
Targeted cancer therapy
TRAF2 protein
Transgenic animals
Transgenic mice
Tumor cells
Tumor Microenvironment
Tumor necrosis factor-TNF
Tumor-Associated Macrophages - immunology
Tumors
tumor‐associated macrophage
tumor‐associated macrophage
M2 macrophage
tumor microenvironment
M1 macrophage
immunotherapy
tumor-associated macrophage
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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. Synopsis Tumor‐associated macrophages (TAMs) are highly immunosuppressive. A high‐throughput drug screening was performed to identify FDA‐approved drugs that can reprogram TAMs into immunostimulatory M1 macrophages. Carfilzomib, together with two other protease inhibitors, was identified as capable of reprogramming M2 into M1 macrophages. ER stress‐IRE1a‐TRAF2‐NF‐kappa B axis was found responsible for the reprogramming. Carfilzomib treatment effectively shrinks autochthonous lung cancers in a transgenic mouse model. Carfilzomib synergized with PD‐1 antibody to completely regress autochthonous lung cancers in mice. Graphical Abstract Tumor‐associated macrophages (TAMs) are highly immunosuppressive. A high‐throughput drug screening was performed to identify FDA‐approved drugs that can reprogram TAMs into immunostimulatory M1 macrophages.
AbstractList 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.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.
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.
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. Synopsis Tumor‐associated macrophages (TAMs) are highly immunosuppressive. A high‐throughput drug screening was performed to identify FDA‐approved drugs that can reprogram TAMs into immunostimulatory M1 macrophages. Carfilzomib, together with two other protease inhibitors, was identified as capable of reprogramming M2 into M1 macrophages. ER stress‐IRE1a‐TRAF2‐NF‐kappa B axis was found responsible for the reprogramming. Carfilzomib treatment effectively shrinks autochthonous lung cancers in a transgenic mouse model. Carfilzomib synergized with PD‐1 antibody to completely regress autochthonous lung cancers in mice. Tumor‐associated macrophages (TAMs) are highly immunosuppressive. A high‐throughput drug screening was performed to identify FDA‐approved drugs that can reprogram TAMs into immunostimulatory M1 macrophages.
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.
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. Synopsis Tumor‐associated macrophages (TAMs) are highly immunosuppressive. A high‐throughput drug screening was performed to identify FDA‐approved drugs that can reprogram TAMs into immunostimulatory M1 macrophages. Carfilzomib, together with two other protease inhibitors, was identified as capable of reprogramming M2 into M1 macrophages. ER stress‐IRE1a‐TRAF2‐NF‐kappa B axis was found responsible for the reprogramming. Carfilzomib treatment effectively shrinks autochthonous lung cancers in a transgenic mouse model. Carfilzomib synergized with PD‐1 antibody to completely regress autochthonous lung cancers in mice. Graphical Abstract Tumor‐associated macrophages (TAMs) are highly immunosuppressive. A high‐throughput drug screening was performed to identify FDA‐approved drugs that can reprogram TAMs into immunostimulatory M1 macrophages.
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. Tumor‐associated macrophages (TAMs) are highly immunosuppressive. A high‐throughput drug screening was performed to identify FDA‐approved drugs that can reprogram TAMs into immunostimulatory M1 macrophages.
Author Luan, Zhidong
Li, Yingchang
Huang, Yadong
Chen, Liang
Liu, Jin
Liang, Jinxia
Zhou, Penghui
Chen, Wensheng
Yang, Tong
Xu, Qigui
Li, Bo
Yuan, Sujing
Zhou, Qian
Wang, Weida
Xia, Zhongjun
Fan, Zhenzhen
Xu, Meng
AuthorAffiliation 6 Guangdong Province Key Laboratory of Bioengineering Medicine Jinan University Guangzhou China
2 MOE Key Laboratory of Glucolipid Metabolic Diseases Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine College of Chinese Medicine Research Guangdong Pharmaceutical University Guangzhou China
1 Key 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 University Guangzhou China
3 State Key Laboratory of Oncology in Southern China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou China
4 Department of Oncology The First Affiliated Hospital Jinan University Guangzhou China
5 Translational medicine laboratory People’s Hospital of Yangjiang City Guangdong China
AuthorAffiliation_xml – name: 1 Key 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 University Guangzhou China
– name: 6 Guangdong Province Key Laboratory of Bioengineering Medicine Jinan University Guangzhou China
– name: 3 State Key Laboratory of Oncology in Southern China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou China
– name: 4 Department of Oncology The First Affiliated Hospital Jinan University Guangzhou China
– name: 2 MOE Key Laboratory of Glucolipid Metabolic Diseases Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine College of Chinese Medicine Research Guangdong Pharmaceutical University Guangzhou China
– name: 5 Translational medicine laboratory People’s Hospital of Yangjiang City Guangdong China
Author_xml – sequence: 1
  givenname: Qian
  orcidid: 0000-0002-2249-0739
  surname: Zhou
  fullname: Zhou, Qian
  email: zhouqian_whu@163.com
  organization: Key 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 University
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  givenname: Jinxia
  surname: Liang
  fullname: Liang, Jinxia
  organization: Key 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 University
– sequence: 3
  givenname: Tong
  surname: Yang
  fullname: Yang, Tong
  organization: Key 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 University
– sequence: 4
  givenname: Jin
  surname: Liu
  fullname: Liu, Jin
  organization: Key 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 University
– sequence: 5
  givenname: Bo
  surname: Li
  fullname: Li, Bo
  organization: Key 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 University, MOE Key Laboratory of Glucolipid Metabolic Diseases, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, College of Chinese Medicine Research, Guangdong Pharmaceutical University
– sequence: 6
  givenname: Yingchang
  surname: Li
  fullname: Li, Yingchang
  organization: Key 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 University
– sequence: 7
  givenname: Zhenzhen
  orcidid: 0000-0002-3769-5286
  surname: Fan
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– sequence: 8
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  surname: Chen
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  givenname: Sujing
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  organization: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer Center
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  givenname: Meng
  surname: Xu
  fullname: Xu, Meng
  organization: Department of Oncology, The First Affiliated Hospital, Jinan University
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  surname: Xu
  fullname: Xu, Qigui
  organization: Translational medicine laboratory, People’s Hospital of Yangjiang City
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  surname: Luan
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  organization: Translational medicine laboratory, People’s Hospital of Yangjiang City
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  organization: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‐sen University Cancer Center
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– sequence: 17
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  orcidid: 0000-0001-7300-6604
  surname: Chen
  fullname: Chen, Liang
  email: chenliang@jnu.edu.cn
  organization: Department of Oncology, The First Affiliated Hospital, Jinan University, Guangdong Province Key Laboratory of Bioengineering Medicine, Jinan University
BackLink https://www.ncbi.nlm.nih.gov/pubmed/34898004$$D View this record in MEDLINE/PubMed
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Issue 1
Keywords tumor‐associated macrophage
M2 macrophage
tumor microenvironment
M1 macrophage
immunotherapy
tumor-associated macrophage
Language English
License Attribution
2021 The Authors. Published under the terms of the CC BY 4.0 license.
This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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  publication-title: Am J Cancer Res
– ident: e_1_2_10_17_1
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SSID ssj0065618
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Snippet 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...
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...
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...
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SubjectTerms Animals
Antibodies
Antigen (tumor-associated)
Bone marrow
Cancer therapies
Cellular Reprogramming
Cytokines
Drug dosages
EMBO03
EMBO19
Endoribonucleases
Experiments
FDA approval
Humans
Immune checkpoint
Immune Checkpoint Inhibitors - pharmacology
Immune system
immunotherapy
Inhibitor drugs
Kinases
Ligands
Lung cancer
Lung Neoplasms - drug therapy
Lymphocytes
Lymphocytes T
M1 macrophage
M2 macrophage
Macrophages
Mice
Mice, Transgenic
Multiple myeloma
Oligopeptides - pharmacology
Patients
Protein folding
Protein Serine-Threonine Kinases
Proteins
Solid tumors
Targeted cancer therapy
TRAF2 protein
Transgenic animals
Transgenic mice
Tumor cells
Tumor Microenvironment
Tumor necrosis factor-TNF
Tumor-Associated Macrophages - immunology
Tumors
tumor‐associated macrophage
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Title Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer
URI https://link.springer.com/article/10.15252/emmm.202114502
https://onlinelibrary.wiley.com/doi/abs/10.15252%2Femmm.202114502
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Volume 14
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