Abstract 5352: SOX9-dependent immune microenvironment remodeling drives KRAS-induced lung adenocarcinoma progression

Abstract

Abstract Interactions between tumor intrinsic factors and tumor microenvironment play a vital role in disease progression and treatment response. SOX9, a transcription factor crucial for tissue development and homeostasis, has been linked to the advancement of tumor growth. However, its specific role as a driver in lung adenocarcinoma (LUAD) is not well-defined. Additionally, the impact of SOX9 on the tumor microenvironment has not been previously explored. We here identify SOX9 transcription factor to play a critical role in defining tumor immune microenvironment and driving disease progression. We employed CRISPR/Cas9 and Cre-LoxP gene knockout methods within the Kras G12D-induced mouse model of lung adenocarcinoma (LUAD). Our objective was to investigate the mechanisms through which SOX9 contributes to the development and advancement of lung adenocarcinoma. To substantiate our findings, we conducted immune profiling, gene expression analyses, RT-qPCR, and immunohistochemistry assessments in the Kras G12D-driven murine LUAD. These results were subsequently validated by examining bulk and single-cell gene expression profiles, as well as immunohistochemistry, in human lung adenocarcinoma. Our studies indicated that SOX9 played a very important role by enhancing lung tumor development, burden, and progression, leading to lower overall survival. SOX9. SOX9 consistently facilitated the growth of organoids in vitro. However, the promotion of tumor growth by SOX9 was notably reduced in immunocompromised mice compared to syngeneic mice. SOX9 demonstrated a suppressive effect on immune cell infiltration, particularly affecting the functionality of tumor-associated CD8+ T cells, natural killer cells, and dendritic cells. CD8+ T cells in the SOX9 overexpressing tumors showed upregulation of exhaustion markers. SOX9-mediated tumor growth advantage could not be observed in the CD8 knockout mice model, suggesting a CD8+ T cell-dependent role. In addition, SOX9 significantly upregulated collagen-related gene expression, leading to a substantial increase in collagen fibers possibly affecting the migration of immune cells into the tumor microenvironment. Together, our studies indicate that SOX9 plays a very critical role in modulating tumor microenvironment by controlling immune cell infiltration and CD8+ T cell exhaustion driving Kras G12D- driven lung tumor progression. Citation Format: Dinoop Ravindran Menon, Hua Zhong, Shridar Ganesan, Hatim Sabaawy, Sharon Pine. SOX9-dependent immune microenvironment remodeling drives KRAS-induced lung adenocarcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5352.