Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity

Lukas M Braun¹, Sophie Giesler², Geoffroy Andrieux³, Roxane Riemer², Nana Talvard-Balland², Sandra Duquesne², Tamina Rückert¹, Susanne Unger⁴, Stefanie Kreutmair⁴, Melissa Zwick¹, Marie Follo², Alina Hartmann², Natascha Osswald², Wolfgang Melchinger², Stefanie Chapman², James A Hutchinson⁵, Sebastian Haferkamp⁶, Leopold Torster⁷, Julian Kött⁷, Christoffer Gebhardt⁷, Dirk Hellwig⁸, Nikolaos Karantzelis², Till Wallrabenstein², Theresa Lowinus², Mehtap Yücel², Niklas Brehm², Justyna Rawluk², Dietmar Pfeifer², Peter Bronsert⁹, Manuel Rogg⁹, Sven Mattern¹⁰, Mathias Heikenwälder¹¹, Stefano Fusco¹², Nisar P Malek¹², Stephan Singer¹³, Annette Schmitt-Graeff¹⁴, Fatih Ceteci¹⁵, Florian R Greten¹⁵, Bruce R Blazar¹⁶, Melanie Boerries¹⁷, Natalie Köhler¹⁸, Justus Duyster¹⁹, Gabriele Ihorst²⁰, Silke Lassmann⁹, Philip Keye²¹, Susana Minguet²², Dirk Schadendorf²³, Selma Ugurel²⁴, David Rafei-Shamsabadi²⁵, Robert Thimme²⁶, Peter Hasselblatt²⁶, Bertram Bengsch²⁷, Christoph Schell⁹, Erika L Pearce²⁸, Frank Meiss²⁵, Burkhard Becher⁴, Carolin Funke-Lorenz²⁴, Jan-Malte Placke²⁴, Petya Apostolova²⁹, Robert Zeiser³⁰

Affiliations

¹ Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
² Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³ Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴ Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
⁵ Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
⁶ Department of Dermatology, University Hospital Regensburg, Regensburg, Germany.
⁷ Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁸ Department of Nuclear Medicine, University Hospital Regensburg, Regensburg, Germany.
⁹ Institute of Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹⁰ Institute of Pathology, University Hospital Tübingen, 72076 Tübingen, Germany.
¹¹ Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; M3 Research Center, Eberhard Karls University Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
¹² Medizinische Klinik I, Uniklinik Tübingen, Tübingen, Germany.
¹³ Institute of Pathology, University Hospital Tübingen, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
¹⁴ University of Freiburg, Freiburg, Germany.
¹⁵ Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany.
¹⁶ Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States.
¹⁷ Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany.
¹⁸ Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
¹⁹ Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany.
²⁰ Clinical Trials Unit, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²¹ Eye Center, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²² Signalling Research Centres BIOSS and CIBSS, Freiburg. Germany. Department of Synthetic Immunology, Faculty of Biology and Centre for Chronic Immunodeficiency (CCI), Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²³ Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany; National Center for Tumor Diseases (NCT)-West, Campus Essen, & Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany.
²⁴ Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany.
²⁵ Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²⁶ Department of Internal Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²⁷ German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Department of Internal Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
²⁸ Department of Oncology, The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
²⁹ Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Department of Oncology, The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Biomedicine, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland; Division of Hematology, University Hospital Basel, Basel, Switzerland. Electronic address: petya.apostolova@unibas.ch.
³⁰ Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Signalling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany. Electronic address: robert.zeiser@uniklinik-freiburg.de.

PMID: 39933899
DOI: 10.1016/j.ccell.2025.01.004

Free article

Clinical Trial

Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity

Lukas M Braun et al. Cancer Cell. 2025.

Free article

. 2025 Feb 10;43(2):269-291.e19.

doi: 10.1016/j.ccell.2025.01.004.

Authors

Affiliations

¹ Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
² Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³ Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴ Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
⁵ Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
⁶ Department of Dermatology, University Hospital Regensburg, Regensburg, Germany.
⁷ Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁸ Department of Nuclear Medicine, University Hospital Regensburg, Regensburg, Germany.
⁹ Institute of Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹⁰ Institute of Pathology, University Hospital Tübingen, 72076 Tübingen, Germany.
¹¹ Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; M3 Research Center, Eberhard Karls University Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
¹² Medizinische Klinik I, Uniklinik Tübingen, Tübingen, Germany.
¹³ Institute of Pathology, University Hospital Tübingen, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
¹⁴ University of Freiburg, Freiburg, Germany.
¹⁵ Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany.
¹⁶ Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States.
¹⁷ Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany.
¹⁸ Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
¹⁹ Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany.
²⁰ Clinical Trials Unit, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²¹ Eye Center, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²² Signalling Research Centres BIOSS and CIBSS, Freiburg. Germany. Department of Synthetic Immunology, Faculty of Biology and Centre for Chronic Immunodeficiency (CCI), Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²³ Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany; National Center for Tumor Diseases (NCT)-West, Campus Essen, & Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany.
²⁴ Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany.
²⁵ Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²⁶ Department of Internal Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²⁷ German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Department of Internal Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
²⁸ Department of Oncology, The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
²⁹ Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Department of Oncology, The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Biomedicine, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland; Division of Hematology, University Hospital Basel, Basel, Switzerland. Electronic address: petya.apostolova@unibas.ch.
³⁰ Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Signalling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany. Electronic address: robert.zeiser@uniklinik-freiburg.de.

PMID: 39933899
DOI: 10.1016/j.ccell.2025.01.004

Abstract

Immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development. A prospective phase-1b/2 trial (EudraCT-No.2021-002073-26) with 14 patients reveals low ECP-related toxicity. Overall response rate for all irAEs is 92% (95% confidence interval [CI]: 63.97%-99.81%); colitis-specific complete remission rate is 100% (95% CI: 63.06%-100%). Glucocorticosteroid dosages could be reduced for all patients after ECP therapy. The ECP-adiponectin axis reduces intestinal tissue-resident memory T cell activation and CD4⁺IFN-γ⁺ T cells in patients with ICI-induced colitis without evidence of loss of anti-tumor immunity. In conclusion, we identify adiponectin as an immunomodulatory molecule that controls ICI-induced irAEs without blocking anti-tumor immunity.

Keywords: adiponectin; anti-tumor immunity; arginase-1; cancer immunotherapy; colitis; extracorporeal photopheresis; immune checkpoint inhibition; immune-related adverse events; immunomodulation; immunosuppression.

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Conflict of interest statement

Declaration of interests P.A. received honoraria from Jazz Pharmaceuticals and Novartis; travel support from Jazz Pharmaceuticals and Takeda. C.G. serves as consultant, advisory board member and/or speaker and received honoraria from BioNTech, BMS, Delcath, Immatics, Immunocore, Iovance, MSD, Novartis, Pierre Fabre, Regeneron, Sanofi, SkylineDX, SUN Pharma, and Sysmex; travel support from BMS, Pierre Fabre, and Sun Pharma; C.G. has unpaid board roles with DeCOG, the German Skin Cancer Foundation, and the Roggenbuck Foundation; and is the co-founder and shareholder of Dermagnostix and Dermagnostix R&D. S.L. received a research grant from BMS and advisory board/speaker invitation from AstraZeneca, Eli Lily, Roche, and Takeda. D.S. served as a consultant, advisory board and/or speaker and received honoraria from Amgen, Array, BMS, Helsinn, Immunocore, InflarX, MSD, Merck-Serono, Nektar, Novartis, OncoSec, Pfizer, Philogen, Regeneron, Replimune, Sandoz, Sanofi, Sunpharma, and 4SC; travel support from BMS, MSD, Merck-Serono, Nektar, Novartis, Pierre Fabre, Sandoz, Sanofi, and 4SC. F.M. served as a consultant and/or received honoraria from Novartis, Roche, BMS, MSD, Pierre Fabre, Sanofi Genzyme, and Sunpharma; travel support from Novartis, Sunpharma, and Bristol-Myers Squibb. S. Ugurel received research support from BMS and Merck Serono, speakers/advisory honoraria from BMS, MSD, Merck Serono, and Novartis; travel support from BMS, MSD, and Pierre Fabre. S.G. has received honoraria from Jazz Pharmaceuticals. C.F.-L. received honoraria and travel support from Therakos/Mallinckrodt. J.-M.P. served as a consultant and/or has received honoraria from BMS, Novartis, and Sanofi; travel support from BMS, Novartis, Pierre Fabre, and Therakos. R.Z. has received honoraria from Novartis, Incyte, Sanofi, and Mallinckrodt. All honoraria and support were outside this work. All other authors declare no conflict of interest. The clinical study was financially supported by Mallinckrodt Pharmaceuticals as an external collaborative research grant.

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Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity

Affiliations

Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials