Identifying targets of precancerous neoantigen-specific T cell surveillance in patients with Lynch syndrome and immune suppression programs supporting colorectal cancer progression 3671

Abstract Description Pathogenic germline variants in mismatch repair (MMR) genes, or Lynch syndrome (LS), increases patients’ risk of developing colorectal cancer (CRC). We previously identified shared, frameshift (fs)-neoantigens in MMR deficient (MMRd) cancers. We hypothesized that T cell surveillance occurs early in CRC development in LS but T cell activity is abrogated by immune regulatory programs during tumor progression. Blood and normal, precancerous (adenoma), and CRC tissues were analyzed from a cohort of 92 LS patients. We leveraged a custom neoantigen-discovery pipeline, functional antigen recognition assays, T cell receptor sequencing, and single cell and spatial transcriptomics. This identified for the first time T cells recognizing shared fs-neoantigens expressed in normal mucosa, adenomas, and tumors of LS patients. Immune editing was evidenced by i) distinct neoantigen repertoires in precancerous tissues compared to tumors and ii) recurrence of low affinity (but not high affinity) neoantigens in later lesions captured from the same patients. Transcriptomic and ex vivo functional analysis revealed that T cells in tumors, relative to precancerous tissues, had reduced functional capacity associated with an infiltration of immunoregulatory myeloid cells (tumor-associated neutrophils and TREM1+ macrophages) which can be therapeutically targeted in future clinical studies. Finally, these shared, precancerous fs-neoantigens can serve as vaccine targets to prevent MMRd cancer in LS. Funding Sources Supported by NIH UG3CA290517 and the Parker Institute for Cancer Immunotherapy Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)