SLAMF7 (CD319) enhances cytotoxic T-cell differentiation and sensitizes CD8⁺ T cells to immune checkpoint blockade

Jan-Erik Sander Sander¹Irina Han¹Lisette Fickenscher¹Jörg-Peter Schmidt²Hartmut Kroll²Tereza Vosikova³Martin Durisin³Holger Lingel¹Monika C. Brunner-Weinzierl^1*

• ¹Department of Experimental Pediatrics, Faculty of Medicine, University Hospital Magdeburg, Magdeburg, Germany
• ²Institute for Transfusion Medicine Dessau, Red Cross Blood Transfusion Service NSTOB, Dessau-Roßlau, Germany
• ³Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, University Hospital Magdeburg, Magdeburg, Germany

Tumors frequently evade immune destruction by impairing cytotoxic CD8 + T-cell responses, highlighting the need for strategies that restore T-cell functionality. Here, we identify SLAMF7 (CD319) as a key enhancer of human CD8 + T-cell responses against tumors. SLAMF7 expression is induced by pro-inflammatory signals such as IL-12 and CD28 co-stimulation. Agonistic SLAMF7 signaling, in synergy with TCR activation, is able to strongly induce T-cell activation and clonal expansion, a finding consistently observed in CD8 + T cells from healthy adults as well as derived from blood and tumor-draining lymph nodes of patients with head and neck squamous cell carcinoma (HNSCC). Moreover it drives a distinct differentiation programme characterized by elevated expression of key transcription factors Eomes and T-bet, leading to increased production of effector molecules such as Interferon , Granzyme B and Perforin. In contrast to CD28 costimulation, SLAMF7 activation also promotes serial killing potential via BTLA induction. In antigen-specific human models, SLAMF7 activation boosts CD8 + T-cell responses against the tumor-associated antigen NY-ESO-1, a key target in several cancers including HNSCC. Moreover, combining SLAMF7 activation with PD-1/PD-L1 immune checkpoint blockade synergistically enhances cytokine release and cytotoxic potential, highlighting its potential to overcome immunosuppression and reinvigorate antitumor immunity.