Abstract B013: Hallmarks of progression in early neoantigen-expressing lung adenocarcinoma
Authors: Bansal Ishan , Loza Jennifer , Hunt Brian G. , Connolly Kelli , Venkatesan Srividhya , Joshi Nikhil 
Published: November 2024

Abstract
Lung adenocarcinoma (LUAD) is the leading cause of cancer-related mortality, largely due to its high prevalence rate and limited therapeutic options. Immunotherapy remains one of the most promising therapeutic avenues, yet further research is necessary to enhance therapy effectiveness for a broader range of patients. Central to the mechanism of immunotherapy is the detection of tumor neoantigens by cytotoxic T cells, which trigger the elimination of tumor cells. However, it is largely unknown how the early interaction between T cells and neoantigen-expressing tumor cells affects the acquisition of cancer hallmarks and tumor progression. To study this, our lab has developed the iNversion-INduced Joined neoAntigen (NINJA) genetically engineered mouse model in which we can initiate expression of a neoantigen in Kras-mutant, Trp53-null, tdTomato-expressing lung adenocarcinoma cells (KPT-NINJA). This system enables us to analyze tumor initiation, progression, and advanced LUAD development over 20 weeks in both neoantigen-expressing and non-expressing tumors. We defined cancer hallmark acquisition and tumor progression in our model by using a combination of multiplex immunofluorescence and computational algorithms to quantify tumor size, immune infiltration, metastasis, and expression of cancer molecular markers p-ERK and Ki67. We isolated tumor cell and immune cell subsets using neural networks to segment cells and tumor structures and used the colocalization of molecular markers to confirm the identity of various cell types. Our initial data validated that within immunogenic tumors there is an increase of T cell infiltration in tumors and have found immunogenic tumors are associated with overall smaller tumors at early time points. Interestingly, these tumors are associated with a decrease in p-ERK expression, suggesting immune infiltration is negatively correlated with p-ERK expression and tumor size. Together, these data indicate that increased immunogenic pressure may be disrupting early tumor proliferation and hallmark progression, shaping the trajectory of development at a very early stage. We are also correlating other molecular markers of tumor progression with immune infiltration, such as Ki67 expression, which we will colocalize with the other findings to construct a model of how tumors acquire hallmark capabilities from an immunogenic perspective. By isolating the mechanism of early tumor progression in immunogenic contexts, we can begin to predict disease trajectory. This will contribute to a better understanding of the mechanisms behind immune evasion and may uncover crucial insights to broaden immune therapy efficacy.
Citation Format: Ishan Bansal, Jennifer Loza, Brian G. Hunt, Kelli Connolly, Srividhya Venkatesan, Nikhil Joshi. Hallmarks of progression in early neoantigen-expressing lung adenocarcinoma [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 B013.