MHC-II-restricted neoantigen expression drives tumor infiltration, activation, and maintenance of nonspecific T cells in lung cancer 2251169

Abstract

Cancer mutations can result in the expression of tumor-specific “neoantigens” that are targeted by T cells. Neoantigen expression drives robust T cell infiltration of tumors across cancer models, yet most of these T cells are not specific for the neoantigens and contain both pathogenic and immunosuppressive subsets. We sought to investigate how neoantigen-specific CD4+ T cells orchestrate nonspecific “Passenger” T cell responses within tumors and determine their impact on tumor progression. Our studies used an autochthonous murine model of lung adenocarcinoma (KrasG12D/+; tp53-/-) in which tumors are synchronously initiated via lentiviral delivery of Cre recombinase with neoantigen, and employed flow cytometry, histological analyses, single-cell transcriptomics, and temporal immune cell perturbations. Expression of a single MHC-II-restricted neoantigen (mITGB1) unexpectedly promoted tumor development. mITGB1 expression drove robust intratumoral enrichment of CD4+ and CD8+ Passenger T cells compared to mITGB1-neg controls. A fraction of Passenger T cells in mITGB1+ tumors uniquely displayed hallmarks of antigen experience, clonal expansion, and readily formed aggregates with B cells. Passenger T cells persisted in mITGB1+ tumors for at least three weeks, while lymphocytes in mITGB1-neg tumors rapidly vanished if cells could not traffic from the periphery. Critically, long-term maintenance of Passenger T cells within tumors required continuous expression of the neoantigen. Our study reveals an unappreciated role for neoantigen-specific CD4+ T cells in promoting tumorigenesis and actively coordinating non-specific Passenger T cell responses within tumors. Paradoxically, neoantigen expression may furnish the tumor microenvironment with novel T cell specificities and unlock cell states that support tumor growth alongside populations that work to combat progression. Jane Coffin Childs Fund, Hope Funds for Cancer Research Lymphocyte Differentiation and Peripheral Maintenance (LYM)