Abstract A98: Cancer-associated fibroblasts promote immunosuppression by inducing NOX2-expressing monocytic MDSCs in lung squamous cell carcinoma

Abstract

Abstract Cancer-associated fibroblasts (CAFs) are activated fibroblasts that constitute the stromal component in the tumor microenvironment (TME). Although CAFs have been shown to promote tumor growth and mediate resistance to chemotherapy, their roles and potential mechanisms by which they may contribute to immune suppression in lung squamous cell carcinoma (LSCC) remain largely unexplored. Here, we identified a positive correlation between CAF and monocytic myeloid cell abundances in 501 primary LSCCs by mining the TCGA dataset. We further validated this finding in an independent cohort using imaging mass cytometry and found a significant spatial interaction between CAFs and monocytic myeloid cells in the TME. To delineate the interplay between CAFs and monocytic myeloid cells, we used chemotaxis assays to show that LSCC patient-derived CAFs promoted recruitment of CCR2+ monocytes via CCL2, which could be reversed by CCR2 inhibition. Using a three-dimensional culture system, we found that CAFs polarized monocytes to adopt a myeloid-derived suppressor cell (MDSC) phenotype characterized by robust suppression of autologous CD8+ T-cell proliferation and IFNγ production. To elucidate additional immunosuppressive mechanisms of CAF-educated MDSCs, we performed proteomic profiling and identified the NADPH oxidase 2 (NOX2) complex to be highly enriched in MDSCs. Pharmacologic inhibition of NOX2 activity in CAF-induced MDSCs restored CD8+ T-cell proliferation. Taken together, our study highlights a pivotal role of CAFs in regulating monocyte recruitment and differentiation and demonstrates that NOX2 inhibition abrogates the CAF-MDSC axis, illuminating a potential therapeutic path to reversing the CAF-mediated immunosuppressive microenvironment. Citation Format: Handan Xiang, Carlo Ramil, Josephine Hai, Chunsheng Zhang, Huijun Wang, Amanda A. Watkins, Roshi Afshar, Peter Georgiev, Xuelei Song, Dongyu Sun, Andrey Loboda, Yanlin Jia, Lily Y Moy, An Chi, Philip E. Brandish. Cancer-associated fibroblasts promote immunosuppression by inducing NOX2-expressing monocytic MDSCs in lung squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A98.