Postdoctoral Fellow Koch Inst. for Integrative Cancer Res., MIT Cambridge, Massachusetts, United States
Disclosure(s):
David E. Klawon, PhD, Jr.: No financial relationships to disclose
Introduction/Rationale: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
