A novel PD-L1-targeted shark VNAR single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer
Chimeric antigen receptor (CAR)-T cell therapy shows excellent potency against hematological malignancies, but it remains challenging to treat solid tumors, mainly because of a lack of appropriate antigenic targets and an immunosuppressive tumor microenvironment (TME). The checkpoint molecule progra...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-03-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770522000328 |
| _version_ | 1819121736046608384 |
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| author | Dan Li Hejiao English Jessica Hong Tianyuzhou Liang Glenn Merlino Chi-Ping Day Mitchell Ho |
| author_facet | Dan Li Hejiao English Jessica Hong Tianyuzhou Liang Glenn Merlino Chi-Ping Day Mitchell Ho |
| author_sort | Dan Li |
| collection | DOAJ |
| description | Chimeric antigen receptor (CAR)-T cell therapy shows excellent potency against hematological malignancies, but it remains challenging to treat solid tumors, mainly because of a lack of appropriate antigenic targets and an immunosuppressive tumor microenvironment (TME). The checkpoint molecule programmed death-ligand 1 (PD-L1) is widely overexpressed in multiple tumor types, and the programmed death-ligand 1 (PD-1)/PD-L1 interaction is a crucial mediator of immunosuppression in the TME. Here we constructed a semi-synthetic shark VNAR phage library and isolated anti-PD-L1 single-domain antibodies. Among these VNARs, B2 showed cross-reactivity to human, mouse, and canine PD-L1, and it partially blocked the interaction of human PD-1 with PD-L1. CAR (B2) T cells specifically lysed human breast cancer and liver cancer cells by targeting constitutive and inducible expression of PD-L1 and hindered tumor metastasis. Combination of PD-L1 CAR (B2) T cells with CAR T cells targeted by GPC3 (a liver cancer-specific antigen) regresses liver tumors in mice. We concluded that PD-L1-targeted shark VNAR single-domain-based CAR-T therapy is a novel strategy to treat breast and liver cancer. This study provides a rationale for potential use of PD-L1 CAR-T cells as a monotherapy or in combination with a tumor-specific therapy in clinical studies. |
| first_indexed | 2024-12-22T06:41:18Z |
| format | Article |
| id | doaj.art-0a9163d299c94f34a13f513042861185 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-22T06:41:18Z |
| publishDate | 2022-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-0a9163d299c94f34a13f5130428611852022-12-21T18:35:26ZengElsevierMolecular Therapy: Oncolytics2372-77052022-03-0124849863A novel PD-L1-targeted shark VNAR single-domain-based CAR-T cell strategy for treating breast cancer and liver cancerDan Li0Hejiao English1Jessica Hong2Tianyuzhou Liang3Glenn Merlino4Chi-Ping Day5Mitchell Ho6Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USALaboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USALaboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USALaboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USALaboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USALaboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USALaboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Corresponding author Mitchell Ho, Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 5002, Bethesda, MD 20892-4264, USA.Chimeric antigen receptor (CAR)-T cell therapy shows excellent potency against hematological malignancies, but it remains challenging to treat solid tumors, mainly because of a lack of appropriate antigenic targets and an immunosuppressive tumor microenvironment (TME). The checkpoint molecule programmed death-ligand 1 (PD-L1) is widely overexpressed in multiple tumor types, and the programmed death-ligand 1 (PD-1)/PD-L1 interaction is a crucial mediator of immunosuppression in the TME. Here we constructed a semi-synthetic shark VNAR phage library and isolated anti-PD-L1 single-domain antibodies. Among these VNARs, B2 showed cross-reactivity to human, mouse, and canine PD-L1, and it partially blocked the interaction of human PD-1 with PD-L1. CAR (B2) T cells specifically lysed human breast cancer and liver cancer cells by targeting constitutive and inducible expression of PD-L1 and hindered tumor metastasis. Combination of PD-L1 CAR (B2) T cells with CAR T cells targeted by GPC3 (a liver cancer-specific antigen) regresses liver tumors in mice. We concluded that PD-L1-targeted shark VNAR single-domain-based CAR-T therapy is a novel strategy to treat breast and liver cancer. This study provides a rationale for potential use of PD-L1 CAR-T cells as a monotherapy or in combination with a tumor-specific therapy in clinical studies.http://www.sciencedirect.com/science/article/pii/S2372770522000328shark VNARsingle-domain antibodyCAR-T cellsimmune checkpointPD-L1triple-negative breast cancer |
| spellingShingle | Dan Li Hejiao English Jessica Hong Tianyuzhou Liang Glenn Merlino Chi-Ping Day Mitchell Ho A novel PD-L1-targeted shark VNAR single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer Molecular Therapy: Oncolytics shark VNAR single-domain antibody CAR-T cells immune checkpoint PD-L1 triple-negative breast cancer |
| title | A novel PD-L1-targeted shark VNAR single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer |
| title_full | A novel PD-L1-targeted shark VNAR single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer |
| title_fullStr | A novel PD-L1-targeted shark VNAR single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer |
| title_full_unstemmed | A novel PD-L1-targeted shark VNAR single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer |
| title_short | A novel PD-L1-targeted shark VNAR single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer |
| title_sort | novel pd l1 targeted shark vnar single domain based car t cell strategy for treating breast cancer and liver cancer |
| topic | shark VNAR single-domain antibody CAR-T cells immune checkpoint PD-L1 triple-negative breast cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2372770522000328 |
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