Control of Tumors by Antigen-Specific CD8+ T Cells through PDL1-Targeted Delivery of Antigenic Peptide
Tumor antigen-specific T cell function is limited by immune tolerance in the tumor microenvironment. In the tumor microenvironment, tumor cells upregulate PD-L1 expression to promote T cell exhaustion by PD-1/PD-L1 interactions and undergo mutations to avoid being targeted by tumor antigen-specific...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2022/9054569 |
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| Summary: | Tumor antigen-specific T cell function is limited by immune tolerance in the tumor microenvironment. In the tumor microenvironment, tumor cells upregulate PD-L1 expression to promote T cell exhaustion by PD-1/PD-L1 interactions and undergo mutations to avoid being targeted by tumor antigen-specific T cells. Thus, tumor cells escape the immune surveillance by causing immune tolerance. We reason that a chimeric molecule made of a PD-L1-specific antibody linked to a cleavable antigenic peptide can target the antigenic peptide to the tumor microenvironment, resulting in the blockade of the PD-1/PD-L1 pathway and killing tumor cells through the coating of antigenic peptide. Here, we have generated a therapeutic chimeric protein containing the PD-L1 single-chain variable fragment (scFv) linked to a cleavable model cytotoxic T lymphocyte (CTL) epitope: E7 CTL peptide. Our study demonstrated that our chimeric protein (named PDL1-scFv-Fc-RE7) can target PD-L1-expressing tumor cells and enable E7 presentation by releasing cleavable E7 CTL peptide to coat tumor cells, resulting in tumor clearance by E7-specific CD8+ T cells. The presentation of the E7 peptide by cancer cells can then render tumor cells susceptible to the killing of preexisting E7-specific CD8+ T cells and contribute to tumor clearance. Our finding suggests a synergistic approach to not only enhance antigen-specific tumor clearance but also bypass immune tolerance. |
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| ISSN: | 2314-7156 |