Eliminating mesothelioma by AAV-vectored, PD1-based vaccination in the tumor microenvironment
The potency of cancer vaccines is often compromised by a variety of immunoinhibitory mechanisms, including stimulation of the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint pathway. Here, to overcome inhibition, we determined the potential of recombinant a...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-03-01
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| Series: | Molecular Therapy: Oncolytics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770521000115 |
| _version_ | 1818613646713946112 |
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| author | Zhiwu Tan Mei Sum Chiu Chi Wing Yan Kwan Man Zhiwei Chen |
| author_facet | Zhiwu Tan Mei Sum Chiu Chi Wing Yan Kwan Man Zhiwei Chen |
| author_sort | Zhiwu Tan |
| collection | DOAJ |
| description | The potency of cancer vaccines is often compromised by a variety of immunoinhibitory mechanisms, including stimulation of the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint pathway. Here, to overcome inhibition, we determined the potential of recombinant adeno-associated virus (rAAV)-vectored, PD1-based vaccination in the tumor microenvironment (TME) to activate antigen-specific T cell responses in the immune-competent murine mesothelioma model. We found that our rAAV-soluble PD1 (sPD1)-TWIST1 vaccine elicited and maintained TWIST1-specific cytotoxic T lymphocyte (CTL) responses and the PD-1 blocker systemically against lethal mesothelioma challenge after intramuscular injection, which was more effective than rAAV-TWIST1 or rAAV-sPD1 alone. More importantly, intratumoral injection of rAAV-sPD1-TWIST1 significantly enhanced immune surveillance by inducing TWIST1-specific CTL responses against vaccine-encoded TWIST1 and bystander gp70-AH1 epitopes, increasing CTL infiltration into the TME and decreasing tumor-associated immunosuppression, leading to complete elimination of established mesothelioma in 5 of 8 tumor-bearing mice. In addition, direct oncosuppression synergized with recruitment of T cells after localized rAAV-sPD1-TWIST1 treatment in a humanized mouse model to inhibit growth of REN human mesothelioma. Our results warrant clinical development of the rAAV-sPD1-TWIST1 vaccine to enhance immunotherapy against a wide range of TWIST1-expressing tumors. |
| first_indexed | 2024-12-16T16:05:26Z |
| format | Article |
| id | doaj.art-6a00c08745d947c1b8cefafbf12ea2af |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-16T16:05:26Z |
| publishDate | 2021-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-6a00c08745d947c1b8cefafbf12ea2af2022-12-21T22:25:22ZengElsevierMolecular Therapy: Oncolytics2372-77052021-03-0120373386Eliminating mesothelioma by AAV-vectored, PD1-based vaccination in the tumor microenvironmentZhiwu Tan0Mei Sum Chiu1Chi Wing Yan2Kwan Man3Zhiwei Chen4AIDS Institute and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR ChinaAIDS Institute and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR ChinaAIDS Institute and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR ChinaDepartment of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR ChinaAIDS Institute and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China; State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, PR China; Corresponding author: Zhiwei Chen, AIDS Institute and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, L5-45, 21 Sassoon Road, Pokfulam, Hong Kong SAR, PR China.The potency of cancer vaccines is often compromised by a variety of immunoinhibitory mechanisms, including stimulation of the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint pathway. Here, to overcome inhibition, we determined the potential of recombinant adeno-associated virus (rAAV)-vectored, PD1-based vaccination in the tumor microenvironment (TME) to activate antigen-specific T cell responses in the immune-competent murine mesothelioma model. We found that our rAAV-soluble PD1 (sPD1)-TWIST1 vaccine elicited and maintained TWIST1-specific cytotoxic T lymphocyte (CTL) responses and the PD-1 blocker systemically against lethal mesothelioma challenge after intramuscular injection, which was more effective than rAAV-TWIST1 or rAAV-sPD1 alone. More importantly, intratumoral injection of rAAV-sPD1-TWIST1 significantly enhanced immune surveillance by inducing TWIST1-specific CTL responses against vaccine-encoded TWIST1 and bystander gp70-AH1 epitopes, increasing CTL infiltration into the TME and decreasing tumor-associated immunosuppression, leading to complete elimination of established mesothelioma in 5 of 8 tumor-bearing mice. In addition, direct oncosuppression synergized with recruitment of T cells after localized rAAV-sPD1-TWIST1 treatment in a humanized mouse model to inhibit growth of REN human mesothelioma. Our results warrant clinical development of the rAAV-sPD1-TWIST1 vaccine to enhance immunotherapy against a wide range of TWIST1-expressing tumors.http://www.sciencedirect.com/science/article/pii/S2372770521000115adeno-associated virusTWIST1 antigenmesotheliomaPD-1PD1-based vaccinationimmune checkpoint blockade |
| spellingShingle | Zhiwu Tan Mei Sum Chiu Chi Wing Yan Kwan Man Zhiwei Chen Eliminating mesothelioma by AAV-vectored, PD1-based vaccination in the tumor microenvironment Molecular Therapy: Oncolytics adeno-associated virus TWIST1 antigen mesothelioma PD-1 PD1-based vaccination immune checkpoint blockade |
| title | Eliminating mesothelioma by AAV-vectored, PD1-based vaccination in the tumor microenvironment |
| title_full | Eliminating mesothelioma by AAV-vectored, PD1-based vaccination in the tumor microenvironment |
| title_fullStr | Eliminating mesothelioma by AAV-vectored, PD1-based vaccination in the tumor microenvironment |
| title_full_unstemmed | Eliminating mesothelioma by AAV-vectored, PD1-based vaccination in the tumor microenvironment |
| title_short | Eliminating mesothelioma by AAV-vectored, PD1-based vaccination in the tumor microenvironment |
| title_sort | eliminating mesothelioma by aav vectored pd1 based vaccination in the tumor microenvironment |
| topic | adeno-associated virus TWIST1 antigen mesothelioma PD-1 PD1-based vaccination immune checkpoint blockade |
| url | http://www.sciencedirect.com/science/article/pii/S2372770521000115 |
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