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Antimesothelioma Immunotherapy by CTLA-4 Blockade Depends on Active PD1-Based TWIST1 Vaccination

Checkpoint immunotherapy is a major breakthrough for cancer treatment, yet its efficacy is often limited against many types of malignancies, including malignant mesothelioma. Considering that the immunotherapeutic efficacy depends on immunosurveillance, we sought to develop an active immunization me...

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Autores principales: Tan, Zhiwu, Chiu, Mei Sum, Yan, Chi Wing, Wong, Yik Chun, Huang, Haode, Man, Kwan, Chen, Zhiwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068049/
https://www.ncbi.nlm.nih.gov/pubmed/32195318
http://dx.doi.org/10.1016/j.omto.2020.01.009
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author Tan, Zhiwu
Chiu, Mei Sum
Yan, Chi Wing
Wong, Yik Chun
Huang, Haode
Man, Kwan
Chen, Zhiwei
author_facet Tan, Zhiwu
Chiu, Mei Sum
Yan, Chi Wing
Wong, Yik Chun
Huang, Haode
Man, Kwan
Chen, Zhiwei
author_sort Tan, Zhiwu
collection PubMed
description Checkpoint immunotherapy is a major breakthrough for cancer treatment, yet its efficacy is often limited against many types of malignancies, including malignant mesothelioma. Considering that the immunotherapeutic efficacy depends on immunosurveillance, we sought to develop an active immunization method to break immune tolerance to tumor self-antigen. Here, we demonstrated that TWIST1, the basic helix-loop-helix transcription factor, was associated with human mesothelioma tumorigenesis and required for the invasion and metastasis of mesothelioma in the immune-competent murine AB1 model. When conventional TWIST1 vaccines were not effective in vivo, programmed cell death protein 1 (PD1)-based vaccination provided prophylactic control by inducing long-lasting TWIST1-specific T cell responses against both subcutaneous and metastatic mesothelioma lethal challenges. Furthermore, while CTLA-4 blockade alone did not show any immunotherapeutic efficacy against established mesothelioma, its combination with PD1-based vaccination resulted in 60% complete remission. Mechanistically, these functional T cells recognized a novel highly conserved immunodominant TWIST1 epitope, exhibited cytotoxic activity and long-term memory, and led to durable tumor regression and survival benefit against established AB1 mesothelioma and 4T1 breast cancer. We concluded that PD1-based vaccination controls mesothelioma by breaking immune tolerance to the tumor self-antigen TWIST1. Our results warrant clinical development of the PD1-based vaccination to enhance immunotherapy against a wide range of TWIST1-expressing tumors.
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spelling pubmed-70680492020-03-19 Antimesothelioma Immunotherapy by CTLA-4 Blockade Depends on Active PD1-Based TWIST1 Vaccination Tan, Zhiwu Chiu, Mei Sum Yan, Chi Wing Wong, Yik Chun Huang, Haode Man, Kwan Chen, Zhiwei Mol Ther Oncolytics Article Checkpoint immunotherapy is a major breakthrough for cancer treatment, yet its efficacy is often limited against many types of malignancies, including malignant mesothelioma. Considering that the immunotherapeutic efficacy depends on immunosurveillance, we sought to develop an active immunization method to break immune tolerance to tumor self-antigen. Here, we demonstrated that TWIST1, the basic helix-loop-helix transcription factor, was associated with human mesothelioma tumorigenesis and required for the invasion and metastasis of mesothelioma in the immune-competent murine AB1 model. When conventional TWIST1 vaccines were not effective in vivo, programmed cell death protein 1 (PD1)-based vaccination provided prophylactic control by inducing long-lasting TWIST1-specific T cell responses against both subcutaneous and metastatic mesothelioma lethal challenges. Furthermore, while CTLA-4 blockade alone did not show any immunotherapeutic efficacy against established mesothelioma, its combination with PD1-based vaccination resulted in 60% complete remission. Mechanistically, these functional T cells recognized a novel highly conserved immunodominant TWIST1 epitope, exhibited cytotoxic activity and long-term memory, and led to durable tumor regression and survival benefit against established AB1 mesothelioma and 4T1 breast cancer. We concluded that PD1-based vaccination controls mesothelioma by breaking immune tolerance to the tumor self-antigen TWIST1. Our results warrant clinical development of the PD1-based vaccination to enhance immunotherapy against a wide range of TWIST1-expressing tumors. American Society of Gene & Cell Therapy 2020-02-08 /pmc/articles/PMC7068049/ /pubmed/32195318 http://dx.doi.org/10.1016/j.omto.2020.01.009 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Tan, Zhiwu
Chiu, Mei Sum
Yan, Chi Wing
Wong, Yik Chun
Huang, Haode
Man, Kwan
Chen, Zhiwei
Antimesothelioma Immunotherapy by CTLA-4 Blockade Depends on Active PD1-Based TWIST1 Vaccination
title Antimesothelioma Immunotherapy by CTLA-4 Blockade Depends on Active PD1-Based TWIST1 Vaccination
title_full Antimesothelioma Immunotherapy by CTLA-4 Blockade Depends on Active PD1-Based TWIST1 Vaccination
title_fullStr Antimesothelioma Immunotherapy by CTLA-4 Blockade Depends on Active PD1-Based TWIST1 Vaccination
title_full_unstemmed Antimesothelioma Immunotherapy by CTLA-4 Blockade Depends on Active PD1-Based TWIST1 Vaccination
title_short Antimesothelioma Immunotherapy by CTLA-4 Blockade Depends on Active PD1-Based TWIST1 Vaccination
title_sort antimesothelioma immunotherapy by ctla-4 blockade depends on active pd1-based twist1 vaccination
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068049/
https://www.ncbi.nlm.nih.gov/pubmed/32195318
http://dx.doi.org/10.1016/j.omto.2020.01.009
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