SLAMF7 (CD319) enhances cytotoxic T-cell differentiation and sensitizes CD8+ T cells to immune checkpoint blockade
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-infla...
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| Format: | Article |
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1654374/full |
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| author | Jan-Erik Sander Irina Han Lisette Fickenscher Jörg-Peter Schmidt Hartmut Kroll Tereza Vosikova Martin Durisin Holger Lingel Monika C. Brunner-Weinzierl |
| author_facet | Jan-Erik Sander Irina Han Lisette Fickenscher Jörg-Peter Schmidt Hartmut Kroll Tereza Vosikova Martin Durisin Holger Lingel Monika C. Brunner-Weinzierl |
| author_sort | Jan-Erik Sander |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1d1f349c03ce4eb7979ac5529b6476a4 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-1d1f349c03ce4eb7979ac5529b6476a42025-08-20T05:32:57ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-08-011610.3389/fimmu.2025.16543741654374SLAMF7 (CD319) enhances cytotoxic T-cell differentiation and sensitizes CD8+ T cells to immune checkpoint blockadeJan-Erik Sander0Irina Han1Lisette Fickenscher2Jörg-Peter Schmidt3Hartmut Kroll4Tereza Vosikova5Martin Durisin6Holger Lingel7Monika C. Brunner-Weinzierl8Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke-University, Magdeburg, GermanyDepartment of Experimental Pediatrics, University Hospital, Otto-von-Guericke-University, Magdeburg, GermanyDepartment of Experimental Pediatrics, University Hospital, Otto-von-Guericke-University, Magdeburg, GermanyInstitute for Transfusion Medicine Dessau, Red Cross Blood Transfusion Service NSTOB, Dessau, GermanyInstitute for Transfusion Medicine Dessau, Red Cross Blood Transfusion Service NSTOB, Dessau, GermanyDepartment of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Otto-von-Guericke-University, Magdeburg, GermanyDepartment of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Otto-von-Guericke-University, Magdeburg, GermanyDepartment of Experimental Pediatrics, University Hospital, Otto-von-Guericke-University, Magdeburg, GermanyDepartment of Experimental Pediatrics, University Hospital, Otto-von-Guericke-University, Magdeburg, GermanyTumors 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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1654374/fullSLAMF familyT-cell differentiationcytotoxicitycostimulationcancerimmunotherapy |
| spellingShingle | Jan-Erik Sander Irina Han Lisette Fickenscher Jörg-Peter Schmidt Hartmut Kroll Tereza Vosikova Martin Durisin Holger Lingel Monika C. Brunner-Weinzierl SLAMF7 (CD319) enhances cytotoxic T-cell differentiation and sensitizes CD8+ T cells to immune checkpoint blockade Frontiers in Immunology SLAMF family T-cell differentiation cytotoxicity costimulation cancer immunotherapy |
| title | SLAMF7 (CD319) enhances cytotoxic T-cell differentiation and sensitizes CD8+ T cells to immune checkpoint blockade |
| title_full | SLAMF7 (CD319) enhances cytotoxic T-cell differentiation and sensitizes CD8+ T cells to immune checkpoint blockade |
| title_fullStr | SLAMF7 (CD319) enhances cytotoxic T-cell differentiation and sensitizes CD8+ T cells to immune checkpoint blockade |
| title_full_unstemmed | SLAMF7 (CD319) enhances cytotoxic T-cell differentiation and sensitizes CD8+ T cells to immune checkpoint blockade |
| title_short | SLAMF7 (CD319) enhances cytotoxic T-cell differentiation and sensitizes CD8+ T cells to immune checkpoint blockade |
| title_sort | slamf7 cd319 enhances cytotoxic t cell differentiation and sensitizes cd8 t cells to immune checkpoint blockade |
| topic | SLAMF family T-cell differentiation cytotoxicity costimulation cancer immunotherapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1654374/full |
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