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

TitleAntimesothelioma Immunotherapy by CTLA-4 Blockade Depends on Active PD1-Based TWIST1 Vaccination
Authors
KeywordsDNA vaccine
TWIST1 antigen
mesothelioma
PD1
soluble PD1-based vaccination
Issue Date2020
PublisherElsevier (Cell Press): OAJ. The Journal's web site is located at https://www.cell.com/molecular-therapy-family/oncolytics/current
Citation
Molecular Therapy - Oncolytics, 2020, v. 16, p. 302-317 How to Cite?
AbstractCheckpoint 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.
Persistent Identifierhttp://hdl.handle.net/10722/289452
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorTan, Z-
dc.contributor.authorChiu, MS-
dc.contributor.authorYan, CW-
dc.contributor.authorWong, YC-
dc.contributor.authorHuang, H-
dc.contributor.authorMan, K-
dc.contributor.authorChen, Z-
dc.date.accessioned2020-10-22T08:12:52Z-
dc.date.available2020-10-22T08:12:52Z-
dc.date.issued2020-
dc.identifier.citationMolecular Therapy - Oncolytics, 2020, v. 16, p. 302-317-
dc.identifier.urihttp://hdl.handle.net/10722/289452-
dc.description.abstractCheckpoint 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.-
dc.languageeng-
dc.publisherElsevier (Cell Press): OAJ. The Journal's web site is located at https://www.cell.com/molecular-therapy-family/oncolytics/current-
dc.relation.ispartofMolecular Therapy - Oncolytics-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectDNA vaccine-
dc.subjectTWIST1 antigen-
dc.subjectmesothelioma-
dc.subjectPD1-
dc.subjectsoluble PD1-based vaccination-
dc.titleAntimesothelioma Immunotherapy by CTLA-4 Blockade Depends on Active PD1-Based TWIST1 Vaccination-
dc.typeArticle-
dc.identifier.emailTan, Z: zwtan@hku.hk-
dc.identifier.emailChiu, MS: carolcms@hku.hk-
dc.identifier.emailHuang, H: hao123@hku.hk-
dc.identifier.emailMan, K: kwanman@hku.hk-
dc.identifier.emailChen, Z: zchenai@hku.hk-
dc.identifier.authorityMan, K=rp00417-
dc.identifier.authorityChen, Z=rp00243-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.omto.2020.01.009-
dc.identifier.pmid32195318-
dc.identifier.pmcidPMC7068049-
dc.identifier.scopuseid_2-s2.0-85081219206-
dc.identifier.hkuros317230-
dc.identifier.volume16-
dc.identifier.spage302-
dc.identifier.epage317-
dc.identifier.eissn2372-7705-
dc.publisher.placeUnited States-

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