1350 Dissecting immune surveillance and escape in Lynch syndrome patients
Year: 2024
Type: conference-abstract
Abstract: Background Patients with Lynch syndrome (LS) harbor germline alterations in the mismatch repair (MMR) genes and are at increased risk of developing colorectal (CRC) and endometrial cancers. These LS tumors are characterized by a high microsatellite instability (MSI-H) phenotype associated with shared immunogenic frameshift (fs)-neoantigen peptides in MSI-H tumors and fs-specific T cell receptors (TCRs) in primary and metastatic MSI-H tumors. Additionally, strong mucosal T cell infiltrates are associated with later CRC onset.1 2 Therefore, we hypothesized that fs-neoantigen-specific T cell surveillance may be observed early in MMR deficient (MMRd) tumor development, but in advanced stages of disease fs-specific T cell activity may be abrogated by immune regulatory programs microenvironment (PCME) and tumor microenvironments (TMEs). Methods Peripheral blood mononuclear cells (PBMCs) and LS normal, precancer (e.g. adenoma) and malignant colon and endometrial tissues were analyzed. Loss of MMR protein expression was assessed with multiplexed immunohistochemistry and immune landscape of PCME and TME with single-cell and spatial transcriptomics. Whole-exome and bulk RNA sequencing were performed to assess fs-neoantigen expression and quality.3 Functional T cell phenotypes and specificity were analyzed with in vitro neoantigen-specific T cell expansion and stimulation assays,4 ex vivo flow cytometry and single-cell RNA/TCR sequencing of PBMCs/MMRd lesions. Results Shared frameshift mutations encoding potentially highly immunogenic peptides are expressed in MMRd normal mucosa, precancerous adenomas, and tumor lesions of LS patients. In peripheral blood, precancerous tissue, and the TME of LS patients, there are T cells capable of recognizing these peptides ex vivo. Fs-encoding mutations that recur in prior MMRd lesions within the same LS patients, as model of prior exposure or vaccination, encode significantly lower MHC binding potential relative to shared fs-neoantigen-encoding mutations that do not recur within patients potentially suggestive of immune editing. T cells in tumors relative to normal/precancerous tissue show reduced functional capacity (transcriptomic and ex vivo stimulation) associated with a polarization toward and infiltration of immunosuppressive innate immune cell subsets. Conclusions We present a preliminary map of the fs-neoantigen landscape in MMRd tumor development in patients with LS and potential evidence of immune dysregulation/suppression programs which may support neoplastic progression. These results also highlight the importance of understanding fs-neoantigen quality and evolution, as well as immune cell differentiation over the course of tumor development, in cancer vaccine design and biomarker selection for immunoprevention efforts. Acknowledgements We would like to thank the patients and their families for participating in our study. We also would like to acknowledge the Mount Sinai Biorepository, Genomics, and Human Immune Monitoring Cores for their assistance in tissue processing and next-generation sequencing assays. We acknowledge funding from the NCI Cancer Immunoprevention Network (CIP-Net). References Roudko V, Cimen Bozkus C, Greenbaum B, Lucas A, Samstein R, Bhardwaj N. Lynch syndrome and MSI-H cancers: from mechanisms to ‘off-the-shelf’ cancer vaccines. Frontiers in Immunology. 2021;12:3946. Bohaumilitzky L, Kluck K, Hüneburg R, Gallon R, Nattermann J, Kirchner M, et al. The different immune profiles of normal colonic mucosa in cancer-free lynch syndrome carriers and lynch syndrome colorectal cancer patients. Gastroenterology. 2022;162:907–19. Roudko V, Bozkus CC, Orfanelli T, McClain CB, Carr C, O’Donnell T, et al. Shared immunogenic poly-epitope frameshift mutations in microsatellite unstable tumors. Cell. 2020;183:1634–49. Cimen Bozkus C, et al. A T-cell-based immunogenicity protocol for evaluating human antigen-specific responses. STAR Protoc, 2021;2(3):100758. Ethics Approval The study was approved by the Icahn School of Medicine at Mount Sinai Institutional Review Board, approval numbers: IRB-19–02392, IRB- 21–01317, and IRB-20–00888.
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W4404064004