1369 Engineering approaches to exploit MHC-II presentation on lung cancer cells

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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 While much effort has been paid to characterize 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 Most immunotherapy approaches rely on endogenous presentation of target antigens in the tumor microenvironment, which can be highly variable and is 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 lung cancer cells to engineer antigen specific responses in the tumor microenvironment. Methods GEMMs, including the KrasLox-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 We demonstrate that LUAD cells present a diverse array of MHC-II peptides in vivo. Remarkably, we found that LUAD cells presented peptides that were derived from exogenous proteins, including those from the tumor microenvironment and systemic circulation. Leveraging this information, we engineered peptide conjugated-antibodies and peptide-loaded nanoparticles to hijack the presentation of exogenous material on LUAD cells. We found that multiple approaches can be utilized to introduce immunogenic MHC-II antigens to be presented directly by MHC-II on LUAD cells. Conclusions These results have profound implications for the implementation of next-generation immunotherapies. Instead of relying on the ability of cancer cells to endogenously present antigenic targets, our approach would enable designer antigens and complementary immunotherapies to be paired in a controlled and deliverable method. 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 1 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-z. Oliveira G, et al. Landscape of helper and regulatory antitumour CD4(+) T cells in melanoma. Nature 2022;605:532–538. https://doi.org:10.1038/s41586-022-04682-5. Alspach 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-y. Jaeger AM, et al. Deciphering the immunopeptidome in vivo reveals new tumour antigens. Nature 2022;607:149–155. https://doi.org:10.1038/s41586-022-04839-2.

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