Abstract 1371: SLAMF9 promotes tumor progression and immunotherapy resistance by reshaping the tumor microenvironment

Abstract Tumor prognosis and immunotherapy efficacy coincides with the infiltration ratio and functional status of immune cells in the tumor microenvironment (TME). Signaling lymphocytes activating molecule factors (SLAMFs) has been reported to play a key role in regulating tumor immunity. Herein, using multi cohorts, in vitro and in vivo experiments, we showed that SLAMF9 worsens tumor and suppresses immune therapy responses by remodeling TME. A pan-cancer analysis showed that SLAMF9 had relatively high transcriptional levels within tumor tissues compared with normal tissues across most cancer types. High SLAMF9 expression is associated with poor prognosis and anti-PD-L1 therapy resistance in advanced clear cell renal cell carcinoma cohorts and metastatic urothelial cancer cohorts. SLAMF9 expression was markedly upregulated in anti-CTLA-4-resistant murine B16 melanoma compared with parental tumors. In particular, SLAMF9 expression was generally negatively correlated with CD8+T cell infiltration score in 12159 patients of 40 cancer types even using different immune cell infiltrating algorithms. Although in vitro experiments have shown that SLAMF9 knockdown has almost no effect on the malignant phenotype of tumor cells, subcutaneous melanoma and lung adenocarcinoma with SLAMF9 deficiency grew slowly, which featured with increased infiltration of CD8+T and PD-1+cells. More importantly, SLAMF9-knockdown significantly increases the sensitivity of subcutaneous melanoma to anti-CTLA-4 inhibitor or anti-PD-L1 antibodies and improved the survival benefits of tumor-bearing mice. This work highlights SLAMF9 as a new target in reshaping the tumor immune microenvironment by controlling the functional status of CD+8 T cells and to improve the efficacy of immunotherapy. Citation Format: Tao Fan, Chu Xiao, Ziqin Deng, Wenpeng Cai, He Tian, Liyu Wang, Chunxiang Li, Jie He. SLAMF9 promotes tumor progression and immunotherapy resistance by reshaping the tumor microenvironment [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 1371.