Scientific Objective and Rationale: Transcription factor p53’s role in regulating the cell cycle, DNA repair, apoptosis, and suppressing tumor development has been well studied; however, the effect of p53 mutation on shaping the cellular microenvironment in which the tumor grows has recently gained attention but has primarily been studied in mouse models. Recent advances in immunotherapies have shown great promise in activating a lung cancer patient’s own anti-tumor immunity and prolonging survival. Such immunotherapies may be particularly effective in p53 mutant lung adenocarcinoma (LUAD) of military personnel that are associated with higher exposure to carcinogens, such as smoking. Hence, better understanding of the tumor microenvironment in p53 mutant LUAD promises to uncover more-effective ways for activating a patient’s own immune system. We propose to use emerging, high-throughput single-cell and spatial technologies to comprehensively characterize the tumor microenvironment of p53 mutant LUAD. We will integrate our data with publicly available data to increase our cohort size to =67 LUAD patients. An increased cohort size will provide us with the necessary statistical power to decipher the cell type expression, tumor regulation, and cell compositions differences of p53 mutant and wildtype LUAD. We will additionally develop new computational methods to model cell-cell interactions and coordinated multicellular gene expression programs that define the tumor microenvironment of p53 mutant LUAD. We will validate our computational modeling by measuring the spatial organization of the tumor microenvironment on matched tissue samples. Given the high frequency of p53 mutation in LUAD (46%), our study will uncover predictive markers that will form the basis of immuno- and combination therapy decisions of the future, will improve our understanding of the cell-cell interactions and mechanisms of immunosuppression, and will identify new innovative, patient-specific strategies for treatment of p53 mutant LUAD.

Career Goals in Lung Cancer Research: My career goal is to contribute to improving the lives of the many patients and families affected by lung cancer, which also took the life of my grandfather. The main focus of my young research laboratory is to use single cell transcriptomic and spatial technologies to build quantitative, predictive models that improve diagnosis, find new druggable pathways, and personalize treatment of patients with lung cancer. The research proposed in this grant aligns perfectly with my lab’s overall vision and my previous training in single cell genomics and lung cancer biology at the Broad Institute, Harvard University, and MIT. The career development award would jumpstart both my career in lung cancer and the important research goals our team seeks to carry out. By incorporating high-dimensional data with computational modeling and expert clinical knowledge available at Mount Sinai and through my career development plan, I believe that our laboratory’s research success will be critical to revolutionizing individual care of lung cancer patients in the near future.

Ultimate Applicability of the Research: The proposed study seeks to use high-dimensional, single-cell, and spatial data to better characterize the cellular heterogeneity, regulatory mechanisms, and tissue architecture of p53 mutant LUAD. In the short term, this study will construct an integrated single-cell and spatial cellular atlas of LUAD across =67 individuals, which will serve as a valuable reference for the lung cancer research community. Moreover, deeper understanding of the regulatory mechanisms and cell-cell interactions that are commonly dysregulated in p53 mutant LUAD will suggest new therapeutic pathways to target. If drugs that can modulate these pathways already exist, our collaborative, clinically minded team at Mount Sinai is well positioned to initiate clinical trials aimed at testing new drug combinations personalized for adenocarcinoma patients with p53 mutation. In the longer term, improved understanding of the cell-cell interactions and mechanisms driving proliferation and immunosuppression in p53 mutant LUAD will also enable the discovery of new drug targets. Our study focuses on p53 mutant LUAD because it is associated with higher rate of tumor mutations encountered in cancers from Veterans that are exposed to higher levels of carcinogens, including tobacco. We believe that our work will have a tangible improvement on the treatment and survival of Service Members, Veterans, and their families during the course of the proposed grant. Our general methodology can be further applied building rational, patient-specific combination therapies for any lung cancer subtype, including rare subtypes that may arise due to unique exposures to carcinogens specifically encountered by military personnel.