Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity
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<sup>+</sup>IFN-γ<sup>+</sup> 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.
Authors
- Alina Hartmann (ORCID: https://orcid.org/0009-0002-0638-0000)
- Florian R. Greten (ORCID: https://orcid.org/0000-0002-3928-6080)
- Silke Laßmann
- Nana Talvard-Balland (ORCID: https://orcid.org/0000-0001-8590-6351)
- Tamina Rückert (ORCID: https://orcid.org/0000-0003-0723-8110)
- Melanie Boerries (ORCID: https://orcid.org/0000-0002-3670-0602)
- Sven Mattern (ORCID: https://orcid.org/0000-0001-7362-0209)
- Dietmar Pfeifer (ORCID: https://orcid.org/0000-0003-2684-5944)
- D. Hellwig (ORCID: https://orcid.org/0000-0002-3056-0143)
- Justyna Rawluk
- Melissa Zwick (ORCID: https://orcid.org/0009-0000-1482-2062)
- Christoffer Gebhardt (ORCID: https://orcid.org/0000-0001-7090-9584)
- Natalie Köhler (ORCID: https://orcid.org/0000-0002-7502-0431)
- Mathias Heikenwälder (ORCID: https://orcid.org/0000-0002-3135-2274)
- Mehtap Yücel (ORCID: https://orcid.org/0000-0001-6091-3205)
- Gabriele Ihorst (ORCID: https://orcid.org/0000-0002-8091-1589)
- Sebastian Haferkamp (ORCID: https://orcid.org/0000-0002-3894-8345)
- Annette Schmitt‐Graeff (ORCID: https://orcid.org/0000-0001-5082-7979)
- David Rafei‐Shamsabadi (ORCID: https://orcid.org/0000-0002-7850-3199)
- Julian Kött (ORCID: https://orcid.org/0000-0003-2073-3909)
- Manuel Rogg (ORCID: https://orcid.org/0000-0002-6658-9159)
- Justus Duyster (ORCID: https://orcid.org/0009-0003-1497-3954)
- Lukas M. Braun (ORCID: https://orcid.org/0000-0003-0770-4994)
- Dirk Schadendorf (ORCID: https://orcid.org/0000-0003-3524-7858)
- Bertram Bengsch (ORCID: https://orcid.org/0000-0003-2552-740X)
- Sandra Duquesne (ORCID: https://orcid.org/0000-0002-9133-6065)
- Stefano Fusco (ORCID: https://orcid.org/0000-0001-6093-4567)
- Petya Apostolova (ORCID: https://orcid.org/0000-0002-3856-5109)
- Jan‐Malte Placke (ORCID: https://orcid.org/0000-0002-7842-4669)
- Nikolaos Karantzelis (ORCID: https://orcid.org/0000-0002-6582-6757)
- Stefanie Kreutmair (ORCID: https://orcid.org/0000-0001-8466-6675)
- Marie Follo (ORCID: https://orcid.org/0000-0002-3090-7442)
- Robert Thimme
- Sophie Giesler (ORCID: https://orcid.org/0000-0002-8146-2199)
- Burkhard Becher (ORCID: https://orcid.org/0000-0002-1541-7867)
- Nisar P. Malek (ORCID: https://orcid.org/0000-0002-9916-4608)
- Philip Keye (ORCID: https://orcid.org/0000-0001-8307-5267)
- Selma Ugurel (ORCID: https://orcid.org/0000-0002-9384-6704)
- Bruce R. Blazar (ORCID: https://orcid.org/0000-0002-9608-9841)
- Frank Meiß (ORCID: https://orcid.org/0000-0002-4044-9094)
- James A. Hutchinson (ORCID: https://orcid.org/0000-0002-1199-4210)
- Geoffroy Andrieux (ORCID: https://orcid.org/0000-0002-5389-9481)
- Erika L. Pearce (ORCID: https://orcid.org/0000-0001-5592-5439)
- Susanne Unger (ORCID: https://orcid.org/0000-0001-6916-7544)
- Wolfgang Melchinger
- R. Kirk Riemer (ORCID: https://orcid.org/0000-0002-3054-9809)
- Peter Bronsert (ORCID: https://orcid.org/0000-0001-8558-0347)
- Fatih Ceteci
- Till Wallrabenstein (ORCID: https://orcid.org/0000-0002-6672-3135)
- Christoph Schell (ORCID: https://orcid.org/0000-0001-5344-624X)
- S. Jonathan Chapman (ORCID: https://orcid.org/0000-0003-3347-6024)
- Leopold Torster (ORCID: https://orcid.org/0000-0003-3637-9342)
- Robert Zeiser (ORCID: https://orcid.org/0000-0001-6565-3393)
- Theresa Lowinus
- Susana Minguet (ORCID: https://orcid.org/0000-0001-8211-5538)
- Peter Hasselblatt (ORCID: https://orcid.org/0000-0002-1107-6516)
- Stephan Singer (ORCID: https://orcid.org/0000-0003-4775-6609)
- Natascha Oßwald (ORCID: https://orcid.org/0009-0003-8095-5287)
- Niklas Brehm
- Carolin Funke-Lorenz
Institutions
- Bloomberg (United States) (US)
- University of Minnesota (US)
- Johns Hopkins University (US)
- Universität Hamburg (DE)
- University of Freiburg (DE)
- German Cancer Research Center (DE)
- University of Basel (CH)
- University of Zurich (CH)
- Heidelberg University (DE)
- University Medical Center Freiburg (DE)
- University Hospital of Basel (CH)
- University Hospital Regensburg (DE)
- Düsseldorf University Hospital (DE)
- Universitätsklinikum Tübingen (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- National Center for Tumor Diseases (DE)
- Essen University Hospital (DE)
- University Children's Hospital Tübingen (DE)
- Georg Speyer Haus (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Heinrich Heine University Düsseldorf (DE)
- University of Duisburg-Essen (DE)
- University of Tübingen (DE)
Publication Details
- Journal
- Cancer Cell
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.ccell.2025.01.004
- Citations
- 36
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 37.63
Funders
- Deutsche Forschungsgemeinschaft
- H2020 European Research Council