Abstract B039: Exploring the impact of neoantigen expression on lung tumor development
Authors: Loza Jennifer L. , Bansal Ishan , Hunt Brian , Connolly Kelli , Jeevanandam Advait , Venkatesan Srividhya , Joshi Nikhil 
Published: November 2024

Lung adenocarcinoma (LUAD) stands as a formidable challenge in oncology, despite the emergence of immunotherapy as a promising treatment avenue. The dynamic interplay between the immune system and cancer plays a pivotal role in shaping cancer development and progression. Central to this process are neoantigens, tumor-specific antigens recognized by cytotoxic T cells, which trigger the elimination of tumor cells. It has been implicated that the presence of T cells also decreases tumor grade. However, the precise impact of neoantigen expression on LUAD development and progression remains poorly understood. Our lab previously developed a genetically engineered mouse model called the iNversion-INduced Joined neoAntigen (NINJA) system with the ability to induce expression of a fluorescent neoantigen in oncogenic KRAS, P53-null, tdTomato-expressing lung adenocarcinoma cells (KPT-NINJA). Using this system, we track tumor initiation, progression, and advanced LUAD development across 20 weeks in both immune-deficient and -sufficient settings. Further, tumors initiated in this system give rise to heterogeneous (neoantigen+ and -) tumors, enabling the study of T cell-driven tumor selection. Through multiplexed immunofluorescence, we identified that neoantigen+ tumors experience increased immune infiltration (CD3+, CD4+, CD8+, B220+) and reduced volume, ultimately leading to prolonged animal survival. Surprisingly, advanced lung tumors maintain neoantigen+ cells, indicating that endogenous lung T cells are ineffective at clearing neoantigen-expressing tumors. Yet, we detected that infiltrated tumors exhibit reduced p-ERK expression, suggesting that T cells may slow tumor progression through a non-cytotoxic mechanism. Transferring stimulated neoantigen-specific T cells to tumor-bearing mice largely eliminated neoantigen+ tumor cells. All these data together suggest complex mechanisms for the role of endogenous T cells in controlling lung tumors. Through molecular characterization of tumor progression and T cell-mediated tumor suppression, this study reveals specific pathways that LUAD cells undergo during the process of development and progression, providing valuable insights into the immune response against neoantigen-expressing tumors. The characterization of early neoantigen-expressing tumor cells is pivotal in validating its utility for studying cancer immunotherapy and identifying key molecular changes during tumor development. Ultimately, by unraveling the intricate interplay between neoantigen expression, immune surveillance, and tumor progression, this project aims to contribute significantly to our understanding of how neoantigens shape the dynamics of tumor biology.

Citation Format: Jennifer L. Loza, Ishan Bansal, Brian Hunt, Kelli Connolly, Advait Jeevanandam, Srividhya Venkatesan, Nikhil Joshi. Exploring the impact of neoantigen expression on lung tumor development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B039.