Title

Building Mouse Models for Tumor Immunology: NINJA in Kras-driven Lung Adenocarcinoma

Date of Award

Spring 2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Joshi, Nikhil

Abstract

Genetically engineered mouse models of tumor immunology frequently require the addition of exogenous neoantigens to trigger immune responses, often within lentiviral vectors that introduce confounding variables. Mouse models with inducible neoantigens avoid some of these problems but have been historically difficult to generate because of leaky expression of antigens in the thymus, resulting in central tolerance in developing CD8 and CD4 T cells. We developed the iNversion INducible Joined neoAntigen (NINJA) mouse model that uses RNA splicing, DNA recombination, and three levels of regulation to prevent neoantigen leakiness and bypass central and peripheral tolerance. We describe the development of these genetic tools and demonstrate their application for studies of tumor immunology. Specifically, we used NINJA to generate an enhanced model of Kras-driven lung adenocarcinoma with robust endogenous anti-tumor T cell responses. We have demonstrated that this KP-NINJA mouse maintains the efficacy of previous models for lung tumor induction, possesses constant levels of neoantigen in each expressing tumor, and generates robust and tumor specific CD8 T cell responses thanks to its unique temporal uncoupling of antigen and tumor induction.

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