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Abstract
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.
Highlights
The ability of tumor cells to downregulate the immune system and avoid recognition by cytotoxic T cells is one of the major barriers for CD8+ T cell-mediated tumor clearance
We demonstrated that the binding of the chimeric PDL1-scFvFc-RE7 protein by PD-L1-expressing tumor cell led to the release of E7-specific cytotoxic T lymphocyte (CTL) epitope and the presentation of the E7 CTL epitope by the major histocompatibility complex (MHC-I) molecules of tumor cells, rendering them susceptible to E7-specific CTL-mediated killing by preexisting E7-specific CD8+ T cells generated by CRTE7 DNA vaccine
Western Blot Analysis Demonstrates the Purity of the PDL1-scFv-Fc-RE7 and PDL1-scFv-Fc Chimeric Proteins
Summary
The ability of tumor cells to downregulate the immune system and avoid recognition by cytotoxic T cells is one of the major barriers for CD8+ T cell-mediated tumor clearance. Mechanisms that result in tumor evasion and immune downregulation include immune suppression and immunoediting [1, 2]. The most well-established immune suppression mechanism relies on the PD-1/PD-L1 axis. PD-L1 (B7-H1; CD274) belongs to the B7 superfamily and is one of the ligands of PD-1, which is expressed on T cells. In order to suppress the immune system, tumor cells often express surface PD-L1 [5]. Since PD-L1 expression can be induced by IFN-γ from lymphocytes, PD-L1 is an important molecule that facilitates tumor escape by suppressing lymphocyte function [6, 7]. Due to the important immune suppressive function of PDL1, many antibody drugs that block the interaction between PD-1 and PD-L1, such as Atezolizumab, Durvalumab, and Avelumab, have been approved by the FDA [8]
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