1280 Lung cancer cells sample local and systemic sources for MHC-II presentation

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Background Central to the success of immunotherapy is antigen presentation on Major Histocompatibility Class I and II (MHC-I and MHC-II). 1 In comparison to MHC-I antigens recognized by CD8+ T cells, our understanding of MHC-II antigens, which are recognized by CD4+ T cells, is far less developed. Notably, there is an increasing appreciation that CD4+ T cell recognition of MHC-II antigens plays a major role in immunotherapy responses, including tumor infiltrating lymphocyte (TIL) therapy and cancer vaccines.2–4 The majority of antigen-specific immunotherapies rely on endogenous presentation of neoantigens, which may be rare, highly variable, and susceptible to immunoediting. Using results obtained from a novel preclinical model of lung adenocarcinoma (LUAD), we propose an alternative immunotherapy strategy that exploits direct MHC-II presentation on LUAD cells harnessing the inherent biological characteristics of MHC-II presentation to engineer antigen specific responses during tumor evolution.Methods GEMMs, including the Kras Lox-stop-Lox-G12D; p53fl/fl (KP), model faithfully recapitulate histopathological features of human LUAD and represent an excellent tool to understand MHC-II in the LUAD microenvironment.5 To profile MHC-II ligands in LUAD, we engineered a Cre-recombinase inducible affinity tagged MHC-II (H2-AbStrep) and incorporated this allele to the KP model (KP/AbStrep), enabling precise isolation of MHC-II peptides from malignant cells in the heterogeneous microenvironment. We thoroughly validated this novel model at the genetic, transcriptomic, and proteomic levels and isolated MHC-II peptides from LUAD tumors in different contexts and with different treatments.Results Remarkably, we observed LUAD cells presenting a diverse array of MHC-II peptides, reinforcing the importance of understanding direct MHC-II presentation on malignant cells. Integration of our peptide data with scRNAseq on timepoint matched KP tumors revealed that LUAD MHC-II peptides were sampled from proteins within the local TME and distal sources from systemic circulation particularly enriching in secreted and membrane resident source proteins. We profiled LUAD presented MHC-II antigens during tumor evolution revealing timepoint specific antigens that reflect temporal alterations in cell identity. Additionally, the MHC-II immunopeptidome can be acutely shifted by blockade of cellular endocytosis and that treatment and tumor evolution influence the presentation of post-translationally modified MHC-II ligands.Conclusions Our model enables comprehensive assessments of the direct presentation of tumor associated antigens through tumor evolution and during targeted perturbations in vivo. Beyond lung cancer, application of the AbStrep system to other disease and tissue contexts will pave the way forward for a deeper understanding of the MHC-II immunopeptidome in vivo to be exploited for next generation immunotherapies.References Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nature Reviews Cancer. 2021;1–15. https://doi.org:10.1038/s41568-021-00339-zOliveira G, et al. Landscape of helper and regulatory antitumour CD4(+) T cells in melanoma. Nature. 2022;605:532–538. https://doi.org:10.1038/s41586-022-04682-5Alspach E, et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature. 2019;574:696–701. https://doi.org:10.1038/s41586-019-1671-8 Creelan BC, et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nature Medicine. 2021;27:1410–1418. https://doi.org:10.1038/s41591-021-01462-yJaeger AM, et al. Deciphering the immunopeptidome in vivo reveals new tumour antigens. Nature. 2022;607:49–55 (2022). https://doi.org:10.1038/s41586-022-04839-2

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