SLAMF7+ CD8+ T cells exhibit decreased anti-tumor responses in renal cell carcinoma

Despite the success of immune-checkpoint inhibitors (ICI) for the treatment of renal cell carcinoma (RCC), many patients fail to receive durable clinical benefits. Therefore, an understanding of resistance to ICIs in RCC is critical for the treatment of this disease. Through single-cell transcriptomic analysis of patient T cells in the HCRN GU16-260 trial, we previously identified a population of CD8+ T cells expressing the SLAMF7 immune receptor that was associated with resistance to nivolumab monotherapy. Here, we functionally interrogated the impact of SLAMF7 overexpression on CD8+ T cell effector functions and found a reduction of pro-inflammatory cytokine and Granzyme B (GzmB) production. CD3+ T cells from healthy human PBMCs were isolated, transduced with either a SLAMF7-GFP or control GFP lentiviral construct, sorted for GFP expression, and subsequently incubated with a SLAMF7 ligand or control. Cytokine and GzmB production were measured using intracellular staining by flow cytometry. SLAMF7-GFP+ CD8+ T cells incubated with a SLAMF7 ligand for 8 hours exhibited a 41.1% reduction in IFN-γ (p=0.0129), 38.3% reduction in IL-2 (p=0.0483), and a 43.8% reduction in GzmB (p=0.0044) production compared to control GFP+ CD8+ T cells. Future work will interrogate the impact of SLAMF7 expression on CD8+ T cell effector functions using patient RCC tumor-infiltrating lymphocytes and evaluate the efficacy of a therapeutic SLAMF7 blocking antibody in restoring anti-tumor functions.