Abstract 5884: Targeting T regulatory cells to intercept progression from preinvasive to invasive lung adenocarcinoma using a novel KRAS-driven murine model

Non-small cell lung cancer is the leading cause of cancer-related death in the US and worldwide, with a 5-year survival of ~18-20%. Understanding of the biology of early lung cancer is necessary to intercept early steps of progression. Indeed, increased utility of low-dose CT guided lung cancer screens in populations at risk have begun to detect early premalignant disease; however, little is known about the underlying biology that drives progression of preinvasive lesions to invasive adenocarcinoma. Moreover, there exists a lack of reliable animal models to assess interception strategies to target disease progression. We have developed and characterized a lung cancer cell-of-origin-specific KRAS-driven mouse model which accurately mirrors progression of human precursor lesions to invasive disease. Transcriptional analysis of preinvasive and invasive stages identified cellular and molecular alternations observed in human lesions, including upregulation of cell proliferation, extracellular matrix remodeling, and an increasingly complex immune microenvironment. Interrogation with immunofluorescence microscopy and Hyperion mass cytometry imaging showed marked reprogramming of the immune microenvironment including increased T cell infiltration and abundance of T regulatory cells (Tregs). Surprisingly, depletion of T cells impaired progression of preinvasive lesions, implicating the critical immunosuppressive roles of Tregs. Spatial transcriptomics (10X Genomics Visium) revealed unique spatial transcriptional changes in the progression from preinvasive to invasive stage disease, including specific ligand-receptor interactions highly expressed in Tregs. Genetic and pharmacological approaches using FoxP3-DTR-GFP mice and low dose cyclophosphamide have begun to define the functional role of Tregs in early premalignant disease. This study demonstrates critical roles of immunosuppressive Tregs in driving progression of preinvasive to invasive lung cancer, and advocates for Treg targeting as a potent immunoprevention approach for patients at risk of developing lung cancer. Citation Format: Mitchell Martin, Michael J. Crowley, Geoffrey Markowitz, Alain Borczuk, Chen Zhang, Liron Yoffe, Arshdeep Singh, Nasser K. Altorki, Vivek Mittal. Targeting T regulatory cells to intercept progression from preinvasive to invasive lung adenocarcinoma using a novel KRAS-driven murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5884.