CD8+ T cell-derived CD40L mediates noncanonical cytotoxicity in CD40-expressing cancer cells
(1) Schiele P (2) Japp AS (3) Stark R (4) Sattelberg JJ (5) Nikolaou C (6) Kornhuber G (7) Abbasi P (8) Ding N (9) Rosnev S (10) Meinke S (11) Mühle K (12) Loyal L (13) Braun J (14) Dingeldey M (15) Durlanik S (16) Matzmohr N (17) Ponikwicka-Tyszko D (18) Wolczynski S (19) Rahman NA (20) Taniuchi I (21) Schlickeiser S (22) Giesecke-Thiel C (23) Blankenstein T (24) Na IK (25) Thiel A (26) Frentsch M
Schiele, Japp, Stark et al. showed that up to half of tumor-specific CD8+ T cells in mice bearing CD40-expressing cancers were CD40L+. CD40L-/-CD8+ T cells transferred into RAG1-/- mice failed to reject CD40+ tumor cells, even when cotransferred with WT CD4+ T cells that expressed CD40L upon activation. CD40 KO, but not CD40L KO, mice rejected CD40+ tumor cells. Human CD40L+CD8+ T cells induced caspase-mediated death of CD40+ human carcinoma cell lines in vitro. A six-gene signature predictive of resistance to CD40-signaled cell death was identified in RCC cell lines and was shown to be associated with a lower survival rate in patients with RCC.
Contributed by Paula Hochman
(1) Schiele P (2) Japp AS (3) Stark R (4) Sattelberg JJ (5) Nikolaou C (6) Kornhuber G (7) Abbasi P (8) Ding N (9) Rosnev S (10) Meinke S (11) Mühle K (12) Loyal L (13) Braun J (14) Dingeldey M (15) Durlanik S (16) Matzmohr N (17) Ponikwicka-Tyszko D (18) Wolczynski S (19) Rahman NA (20) Taniuchi I (21) Schlickeiser S (22) Giesecke-Thiel C (23) Blankenstein T (24) Na IK (25) Thiel A (26) Frentsch M
Schiele, Japp, Stark et al. showed that up to half of tumor-specific CD8+ T cells in mice bearing CD40-expressing cancers were CD40L+. CD40L-/-CD8+ T cells transferred into RAG1-/- mice failed to reject CD40+ tumor cells, even when cotransferred with WT CD4+ T cells that expressed CD40L upon activation. CD40 KO, but not CD40L KO, mice rejected CD40+ tumor cells. Human CD40L+CD8+ T cells induced caspase-mediated death of CD40+ human carcinoma cell lines in vitro. A six-gene signature predictive of resistance to CD40-signaled cell death was identified in RCC cell lines and was shown to be associated with a lower survival rate in patients with RCC.
Contributed by Paula Hochman
ABSTRACT: T cells and their effector functions, in particular the canonical cytotoxicity of CD8(+) T cells involving perforin, granzymes, Fas ligand (FasL), and tumor necrosis factor related apoptosis inducing ligand (TRAIL), are crucial for tumor immunity. Here, we reveal a previously unidentified mechanism by which CD40L-expressing CD8(+) T cells induce cytotoxicity in cancer cells. In murine models, up to 50% of tumor-specific CD8(+) T cells expressed CD40L, and conditional CD40L ablation in CD8(+) T cells alone led to tumor formation. Mechanistically, CD40L(+)CD8(+) T cells can induce cell death in CD40-expressing cancer cells by triggering caspase-8 activation. We demonstrate that a gene signature for resistance to CD40 signaling-induced cell death strongly correlates with worse survival in different human cancer cohorts. Our results introduce CD40L as a rather counterintuitive, noncanonical cytotoxic factor that complements the capabilities of CD8(+) T cells to combat cancers and has the potential to enhance the efficacy of immunotherapies.
Author Info:
(1) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Ger
many. (2) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. Captain T Cell GmbH, 12529 Berlin, Germany. (3) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. Tissue Immunology, BIH Center for Regenerative Therapies, Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. (4) Max-Delbrck-Center for Molecular Medicine and Institute for Immunology, Charit-Universittsmedizin Berlin, 13125 Berlin, Germany. (5) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. (6) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. (7) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. (8) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. (9) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. (10) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. (11) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. (12) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. Si-M/"Der Simulierte Mensch," Technische Universitt Berlin and Charit - Universittsmedizin Berlin, 13353 Berlin, Germany. (13) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. Si-M/"Der Simulierte Mensch," Technische Universitt Berlin and Charit - Universittsmedizin Berlin, 13353 Berlin, Germany. (14) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. Si-M/"Der Simulierte Mensch," Technische Universitt Berlin and Charit - Universittsmedizin Berlin, 13353 Berlin, Germany. (15) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. (16) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. (17) Institute of Biomedicine, University of Turku, 20520 Turku, Finland. Department of Biology and Pathology of Human Reproduction, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-748 Olsztyn, Poland. (18) Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, 15-276 Bialystok, Poland. (19) Institute of Biomedicine, University of Turku, 20520 Turku, Finland. Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, 15-276 Bialystok, Poland. (20) RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan. (21) Institute for Medical Immunology, Charit-Universittsmedizin Berlin, Corporate members of Freie Universitt Berlin and Humboldt-Universitt zu Berlin, Berlin, Germany. (22) Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. (23) Max-Delbrck-Center for Molecular Medicine and Institute for Immunology, Charit-Universittsmedizin Berlin, 13125 Berlin, Germany. (24) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. Department of Hematology, Oncology and Tumor Immunology, and ECRC Experimental and Clinical Research Center, both Charit-Universittsmedizin Berlin, Corporate members of Freie Universitt Berlin and Humboldt-Universitt zu Berlin, Berlin, Germany. German Cancer Consortium (DKTK), Berlin, Germany. ECRC Experimental and Clinical Research Center, Corporate Member of Freie Universitt Berlin and Humboldt Universitt zu Berlin, Charit Universittsmedizin Berlin, Berlin, Germany. (25) Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. Si-M/"Der Simulierte Mensch," Technische Universitt Berlin and Charit - Universittsmedizin Berlin, 13353 Berlin, Germany. (26) Therapy-Induced Remodeling in Immuno-Oncology, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany. Regenerative Immunology and Aging, BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charit-Universittsmedizin Berlin, 13353 Berlin, Germany.
Citation: Sci Adv 2025 May 23 11:eadr9331 Epub05/21/2025
