Unsuccessful checkpoint blockade and vaccination therapy despite expansion of tumor neoantigen-specific CD8 T cells in the Lewis Lung Carcinoma (LLC) model
| Autor: | Shamin Li, Yannick Simoni, Summer Zhuang, Shaokang Ma, Jonathan Chee, Alec Redwood, Bruce Robinson, Evan Newell |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 204:165.13-165.13 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.204.supp.165.13 |
| Popis: | The most promising cancer immunotherapies to date target immune checkpoint receptors, such as PD-1 and CTLA-4. However, T cell checkpoint blockade has no inherent tumor specificity and shows uneven response, with up to 70–80% of patients resistant to these therapies. Here, we use a spontaneous mouse model resistant to immunotherapy to explore how immune checkpoint blockade (ICB) affects tumor-specific T cells and understand why these cells fail to eradicate tumor cells after treatment. Using combinatorial tetramer staining by CyTOF, we identified a new tumor-specific neoantigen in Lewis Lung Carcinoma (LLC). These tumor-specific CD8+ tumor-infiltrating lymphocytes (TILs) strongly exhibit an activation phenotype and can also be detected in different peripheral compartments at lower frequency. Surprisingly, despite an absence of tumor regression, we observed a remarkable expansion of tumor-specific CD8+ TILs after ICB with anti-PD1, anti-CTLA4, or neoantigen peptide vaccination. This expansion is associated with phenotypic changes, including enrichment of exhaustion markers and CD39 expression indicating chronic TCR activation and confirming recognition of tumor cells. Current single-cell RNA sequencing and TCR profiling analysis will correlate transcriptomics and clonality of these tumor-specific T cells after cancer therapies with anti-tumor response and elucidate their functionalities within the tumor microenvironment. Overall this work provides a new model for studying neoantigens in tumors and revisits the role of neoantigen-specific T cells in the context of ICB, which will have important implications in designing future immunotherapeutic strategies. |
| Databáze: | OpenAIRE |
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