A PD-L1-Based Cancer Vaccine Elicits Antitumor Immunity in a Mouse Melanoma Model
Engagement of programmed death 1 receptor (PD-1) and its ligand PD-L1/2 induces a signal transduction pathway that inhibits the activity of tumor-infiltrating cytotoxic T lymphocytes and promotes tumor growth and metastasis. Antibodies blocking PD-1 or PD-L1 can restore antitumor T cell responses an...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-09-01
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| Series: | Molecular Therapy: Oncolytics |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770519300646 |
| _version_ | 1828242134381101056 |
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| author | Zhibing Lin Yan Zhang Huaman Cai Fuqiang Zhou Hongjun Gao Li Deng Rongxiu Li |
| author_facet | Zhibing Lin Yan Zhang Huaman Cai Fuqiang Zhou Hongjun Gao Li Deng Rongxiu Li |
| author_sort | Zhibing Lin |
| collection | DOAJ |
| description | Engagement of programmed death 1 receptor (PD-1) and its ligand PD-L1/2 induces a signal transduction pathway that inhibits the activity of tumor-infiltrating cytotoxic T lymphocytes and promotes tumor growth and metastasis. Antibodies blocking PD-1 or PD-L1 can restore antitumor T cell responses and cause long-term remission in a subset of cancer patients with advanced or refractory tumors. In this study, we asked whether PD-L1 vaccination could confer tumor control in mouse tumor models. To address the central tolerance toward self-molecules, we fused the extracellular domain of PD-L1 (PD-L1E) to the C-terminal of the translocation domain of diphtheria toxin (DTT). DTT is able to elicit CD4+ T cell responses required for inducing robust immune responses against self-molecules. The fusion molecule is called DPDL1E. When formulated with incomplete Freund’s adjuvant (IFA), DPDL1E elicited robust immune responses biased toward the Th1 type and inhibited tumor growth in both preventive and therapeutic mouse tumor models. We further showed that the anti-DPDL1E sera blocked PD-L1 binding to PD-1 in vitro. The DPDL1E vaccination increased the levels of tumor-infiltrating T lymphocytes (TILs) and reduced the levels of myeloid-derived suppressor cells (MDSCs) as well as exhausted LAG3+PD-1+ CD8+ T cells. All of these data suggest that DPDL1E vaccination reverses the suppressive phenotype of the tumor microenvironment and that it is a promising strategy for cancer therapy. Keywords: PD-L1, myeloid-derived suppressor cell, tumor-infiltrating lymphocytes, cancer immunotherapy, tumor microenvironment |
| first_indexed | 2024-04-12T22:11:07Z |
| format | Article |
| id | doaj.art-b41fde2ff96b4f5598ab3ad72303d5f8 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-04-12T22:11:07Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-b41fde2ff96b4f5598ab3ad72303d5f82022-12-22T03:14:46ZengElsevierMolecular Therapy: Oncolytics2372-77052019-09-0114222232A PD-L1-Based Cancer Vaccine Elicits Antitumor Immunity in a Mouse Melanoma ModelZhibing Lin0Yan Zhang1Huaman Cai2Fuqiang Zhou3Hongjun Gao4Li Deng5Rongxiu Li6State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University, Shanghai, ChinaState Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University, Shanghai, ChinaState Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University, Shanghai, ChinaState Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University, Shanghai, ChinaRuikang Hospital Affiliated with Guangxi University of Chinese Medicine, Shanghai, ChinaShanghai HyCharm, Inc., Shanghai, ChinaState Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China; Ruikang Hospital Affiliated with Guangxi University of Chinese Medicine, Shanghai, China; Corresponding author: Rongxiu Li, State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China.Engagement of programmed death 1 receptor (PD-1) and its ligand PD-L1/2 induces a signal transduction pathway that inhibits the activity of tumor-infiltrating cytotoxic T lymphocytes and promotes tumor growth and metastasis. Antibodies blocking PD-1 or PD-L1 can restore antitumor T cell responses and cause long-term remission in a subset of cancer patients with advanced or refractory tumors. In this study, we asked whether PD-L1 vaccination could confer tumor control in mouse tumor models. To address the central tolerance toward self-molecules, we fused the extracellular domain of PD-L1 (PD-L1E) to the C-terminal of the translocation domain of diphtheria toxin (DTT). DTT is able to elicit CD4+ T cell responses required for inducing robust immune responses against self-molecules. The fusion molecule is called DPDL1E. When formulated with incomplete Freund’s adjuvant (IFA), DPDL1E elicited robust immune responses biased toward the Th1 type and inhibited tumor growth in both preventive and therapeutic mouse tumor models. We further showed that the anti-DPDL1E sera blocked PD-L1 binding to PD-1 in vitro. The DPDL1E vaccination increased the levels of tumor-infiltrating T lymphocytes (TILs) and reduced the levels of myeloid-derived suppressor cells (MDSCs) as well as exhausted LAG3+PD-1+ CD8+ T cells. All of these data suggest that DPDL1E vaccination reverses the suppressive phenotype of the tumor microenvironment and that it is a promising strategy for cancer therapy. Keywords: PD-L1, myeloid-derived suppressor cell, tumor-infiltrating lymphocytes, cancer immunotherapy, tumor microenvironmenthttp://www.sciencedirect.com/science/article/pii/S2372770519300646 |
| spellingShingle | Zhibing Lin Yan Zhang Huaman Cai Fuqiang Zhou Hongjun Gao Li Deng Rongxiu Li A PD-L1-Based Cancer Vaccine Elicits Antitumor Immunity in a Mouse Melanoma Model Molecular Therapy: Oncolytics |
| title | A PD-L1-Based Cancer Vaccine Elicits Antitumor Immunity in a Mouse Melanoma Model |
| title_full | A PD-L1-Based Cancer Vaccine Elicits Antitumor Immunity in a Mouse Melanoma Model |
| title_fullStr | A PD-L1-Based Cancer Vaccine Elicits Antitumor Immunity in a Mouse Melanoma Model |
| title_full_unstemmed | A PD-L1-Based Cancer Vaccine Elicits Antitumor Immunity in a Mouse Melanoma Model |
| title_short | A PD-L1-Based Cancer Vaccine Elicits Antitumor Immunity in a Mouse Melanoma Model |
| title_sort | pd l1 based cancer vaccine elicits antitumor immunity in a mouse melanoma model |
| url | http://www.sciencedirect.com/science/article/pii/S2372770519300646 |
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