Tumor-associated Fibrosis leads to an increase in T-cell exhaustion and Impairs Tumor Control in Non-Small Cell Lung Cancer

Abstract Lung cancer is the leading cause of cancer-related mortality with non-small cell lung cancer (NSCLC) being the most predominant type. Recent studies have shown the efficacy of anti-PD1 inhibitors which improved overall survival. However, this efficacy is limited to a subset of patients due to the intrinsic tumor resistance to immune checkpoint inhibitors. Our group recently demonstrated that tumor-associated fibrosis negatively correlates with T cell-mediated immune response in lung cancer. This is largely dependent on Col13a1-expressing cancer-associated fibroblasts (CAFs), which result in recruiting the immunosuppressive macrophages and regulatory T cells while limiting dendritic cells and CD8 T cell infiltration. Here, we characterize the effect of fibrosis on the TME including TILs and macrophages using an orthotopic KRAS and P53-driven murine NSCLC model (KPL86-mCher model) with FITC-induced fibrosis.Fibrosis significantly increased the number of cancer-associated fibroblasts and collagen density in KPL86-mCher lung tumors. Following carboplatin + pemetrexed and Anti-PD1 treatment, we observed no increase in tumor-infiltrating CD4+ and CD8+ T cells or decrease in tumor burden when compared with the non-fibrotic tumors. Rather, we observed a significant increase in exhausted T cells marked by high Tim3, PD1, and TOX in fibrotic KPL86-mCher tumors. Corresponding to these impaired T-cell responses, we found an increase in tumor-infiltrating alveolar macrophages with immunosuppressive phenotype under fibrotic tumor conditions. Our data suggests that tumor-associated fibrosis leads to an increase in CD8+ T cell exhaustion as well as immunosuppressive macrophage infiltration in our spontaneously derived murine model on NSCLC. Overall, this indicates that targeting tumor fibrosis may significantly improve the efficacy of immunotherapy which would have translational implications for patients with immunotherapy-resistant NSCLC. Citation Format: Usman Y. Panni, Varun Shenoy, Brett Knolhoff, Faiz Ahmed, Brett Herzog, William G. Hawkins, John A. Olson, David G. DeNardo. Tumor-associated fibrosis leads to an increase in T-cell exhaustion and impairs tumor control in non-small cell lung cancer [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 1522.