Abstract
Despite impressive clinical success, cancer immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance. Here we use the autochthonous TiRP melanoma model, which recapitulates the tumoral resistance signature observed in human melanomas. TiRP tumors resist immunotherapy based on checkpoint blockade, cancer vaccines or adoptive T-cell therapy. TiRP tumors recruit and activate tumor-specific CD8+ T cells, but these cells then undergo apoptosis. This does not occur with isogenic transplanted tumors, which are rejected after adoptive T-cell therapy. Apoptosis of tumor-infiltrating lymphocytes can be prevented by interrupting the Fas/Fas-ligand axis, and is triggered by polymorphonuclear-myeloid-derived suppressor cells, which express high levels of Fas-ligand and are enriched in TiRP tumors. Blocking Fas-ligand increases the anti-tumor efficacy of adoptive T-cell therapy in TiRP tumors, and increases the efficacy of checkpoint blockade in transplanted tumors. Therefore, tumor-infiltrating lymphocytes apoptosis is a relevant mechanism of immunotherapy resistance, which could be blocked by interfering with the Fas/Fas-ligand pathway.
Highlights
Despite impressive clinical success, cancer immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance
The HRasG12V transgene is followed by an internal ribosome entry site (IRES) and the primers: Trap1a (P1A) coding sequence (Trap1a), so that all melanomas express P1A and are recognized by P1A-specific CD8+ T cells directed against the dominant P1A epitope, a nine-amino acid peptide presented by H-2Ld2
Because TiRP tumors express MAGE-type tumor antigen P1A, we tested a preventive vaccination against P1A using an established prime/boost immunization scheme based on P1Arecombinant adenovirus and Semliki Forest virus (SFV), which induces high levels of P1A-specific CD8+ T cells and significant protection against a challenge injection of P1A-positive tumor cells[6]
Summary
Cancer immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance. Most available GEMM models either do not express defined tumor antigens, precluding in-depth analysis of the anti-tumor immune responses in the course of immunotherapy, or express model antigens such as ovalbumin or viral antigens, which are highly immunogenic and do not reflect the poor immunogenicity of tumor antigens that are naturally expressed on human tumors To circumvent these issues, we created the GEMM model of inducible melanomas expressing P1A, a defined mouse tumor antigen of the MAGE type[55], which we chose as the best representative of the clinically relevant group of human MAGE-type tumor antigens encoded by cancer-germline genes[1]. TIL apoptosis is triggered by Fas-ligand, which is expressed by polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) The latter are enriched in induced TiRP tumors as compared to transplanted isogenic tumors. Administration of soluble Fas-Fc can prevent TIL apoptosis and improve the efficacy of immunotherapy
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