Objectives: CD8⁺ T-cells play a crucial role in combating tumors. However, some tumor microenvironments force them to undergo apoptosis, reducing the overall cytotoxic efficiency of the anti-tumoral response. Despite this pivotal role of apoptosis, the precise regulatory mechanisms underlying this process in CD8⁺ T-cells remain incompletely understood. As SLAMF7 is highly expressed on cytotoxic T-cells, we hypothesize that SLAMF7 signaling in CD8⁺ T-cells confers a protective effect against apoptosis, rendering them functionally superior for tumor lysis.

Methods: Naive CD8⁺ T-cells were stimulated using αCD3 antibodies or peptide antigens of different affinities. Additionally, cells were co-stimulated with CD28 signals and/or agonistic αSLAMF7 antibodies, respectively. Apoptosis was induced by  CD95 cross-linking. Flow cytometry was utilized to analyze the proportion of living/dead cells, Annexin V exposure, and active Caspase 3/7. Mitochondrial membrane potential, as an early apoptosis indicator, was evaluated using JC-1 staining. Further, we analyzed pro- and anti-apoptotic proteins, expression of surface receptors, and conducted mRNA analysis.

Results: Through SLAMF7 activation, CD8⁺ T-cells increased their living cell proportion, particularly in the CD28-triggered compartment. Moreover, they lowered the cell fraction with active caspase 3/7 and disrupted mitochondrial potential, implicating a profound reduction of apoptosis onset. SLAMF7 signaling also affected apoptosis of antigen-specific CD8⁺ T-cells signals, especially those involving low-affinity peptides, thereby improving the lifespan of weakly activated CD8⁺ effector cells. Furthermore, SLAMF7-activated CD8⁺ T-cells downregulated the expression of surface exhaustion markers, such as PD-1 or TNFR1, while upregulating TCF-1 levels, suggesting differentiation towards a stem-like phenotype.

Conclusions: Our study highlights the identification of the SLAMF7 receptor as a promising novel target to reduce CD8⁺ T-cells apoptosis. By decreasing caspase 3/7 activity and stabilizing mitochondrial membrane potential, targeting SLAMF7 provides CD8⁺ T-cells with a competitive advantage in countering tumors within its microenvironment.