Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY/ABSTRACT Driver mutations confer increased fitness to cancer cells but can also encode neoantigens that stimulate an anti- cancer immune response. This anti-tumor immunity is mediated primarily by T cell receptor (TCR) recognition of mutation-derived peptides presented on Human Leukocyte Antigen (HLA) complexes. L858R promotes unchecked growth and is the most common epidermal growth factor receptor (EGFR) mutation in lung cancer, accounting for 40% of all observed mutations in the protooncogene. How L858R may stimulate an anti-tumor immune response is not yet understood. The objective of the proposed work is to understand the mechanisms through which the EGFR L858R mutation affects tumor biology in provoking anti-tumor immunity. My preliminary data show that L858R-derived peptides are capable of binding to and stabilizing HLA-A*03:01 and HLA-A*11:01 complexes. In two orthogonal assays, L858R peptide-HLA (pHLA) complexes stimulate CD8+ T cells more strongly than wild-type EGFR pHLA complexes. Finally, using pHLA multimer flow cytometry, I have identified CD8+ T cells from healthy donor PBMCs that recognize the L858R pHLA complex through their TCRs. I hypothesize that the EGFR L858R mutation generates an immunogenic neoantigen that provokes T cell- mediated anti-tumor immunity due to the high clonality of the mutation. In Aim 1, I will fully define determinants of L858R immunogenicity by characterizing the EGFR L858R-derived neopeptide and its ability to activate T cells. I will employ HLA immunoprecipitation coupled to liquid chromatography mass spectrometry to identify the L858R peptides presented on HLA, determine the relative contributions of CD4+ and CD8+ T cells in the immune response, and examine exhaustion phenotypes in L858R-specific T cells from patients using single cell RNA and TCR sequencing. In Aim 2, I will determine the ability of EGFR L858R-specific T cells to suppress tumor growth. I will also determine how mutation clonality and pHLA expression affect the anti-tumor immune response. This study employs cutting edge genetic tools and computational approaches to generate a detailed understanding of adaptive immunity against somatic mutations in tumors. Furthermore, this proposal is tailored for a physician-scientist in training, as it investigates clinically relevant determinants of a T cell-mediated immune response against EGFR-mutant cancers, and will inform the development of an adoptive T cell therapy for a large subset of lung cancer patients.
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