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A Novel Mouse Model for the Study of Anti-Tumor T Cell Responses in Kras Driven Lung Adenocarcinoma

Kras-driven lung adenocarcinoma (LUAD) is one of the most common forms of lung cancer. A significant fraction of patients with Kras-driven LUAD respond to immunotherapy, but mechanistic studies of immune responses against LUAD have been limited because of a lack of immunotherapy-responsive models. The Kras-Lox-STOP-Lox-G12D p53 flox/flox (KP) model faithfully recapitulates human LUAD but does not elicit tumor-specific T cell responses because developing tumors lack neoantigens. In vivo lentiviral transduction has been used to express neoantigens in KP LUADs but this strategy has limitations. We report here the development of the immunogenic KP x NINJA (iNversion INducible Joined NeoAntigen) (KP-NINJA) LUAD model. This model allows for temporal uncoupling of antigen and tumor induction, which allows one to wait until after adeno/lentiviral infection-induced inflammation has subsided to induce neoantigen expression by tumors. Neoantigen expression is restricted to EPCAM+ epithelial cells, with no neoantigen expression in CD45+ immune cells in the lung. Analysis of neoantigen expression by FACS and immunofluorescence revealed that expression was more consistent between neoantigen+ tumors (~2x variance) than lentiviral-programmed neoantigen+ tumors (>80x variance). Moreover, tumors were infiltrated by tumor-specific CD8 T cells. Finally, LUAD cell lines derived from KP-NINJA mice were immunogenic and responded to immune checkpoint therapy with anti-PD-1 and anti-CTLA4, providing means for future studies into the immunobiology of therapeutic responses in LUAD.