AUTHOR=Sander Jan-Erik , Han Irina , Fickenscher Lisette , Schmidt Jörg-Peter , Kroll Hartmut , Vosikova Tereza , Durisin Martin , Lingel Holger , Brunner-Weinzierl Monika C. 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1654374

DOI=10.3389/fimmu.2025.1654374

ISSN=1664-3224

ABSTRACT=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 γ, 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.