Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity PMID: 39933899

ADC Targets in Oncology

2026-04-10

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

Cancer Cell. 2025 Feb 10;43(2):269-291.e19. doi: 10.1016/j.ccell.2025.01.004.

Lukas M Braun ¹ , Sophie Giesler ² , Geoffroy Andrieux ³ , Roxane Riemer ² , Nana Talvard-Balland ² , Sandra Duquesne ² , Tamina Rückert ¹ , Susanne Unger ⁴ , Stefanie Kreutmair ⁴ , Melissa Zwick ¹ , Marie Follo ² , Alina Hartmann ² , Natascha Osswald ² , Wolfgang Melchinger ² , Stefanie Chapman ² , James A Hutchinson ⁵ , Sebastian Haferkamp ⁶ , Leopold Torster ⁷ , Julian Kött ⁷ , Christoffer Gebhardt ⁷ , Dirk Hellwig ⁸ , Nikolaos Karantzelis ² , Till Wallrabenstein ² , Theresa Lowinus ² , Mehtap Yücel ² , Niklas Brehm ² , Justyna Rawluk ² , Dietmar Pfeifer ² , Peter Bronsert ⁹ , Manuel Rogg ⁹ , Sven Mattern ¹⁰ , Mathias Heikenwälder ¹¹ , Stefano Fusco ¹² , Nisar P Malek ¹² , Stephan Singer ¹³ , Annette Schmitt-Graeff ¹⁴ , Fatih Ceteci ¹⁵ , Florian R Greten ¹⁵ , Bruce R Blazar ¹⁶ , Melanie Boerries ¹⁷ , Natalie Köhler ¹⁸ , Justus Duyster ¹⁹ , Gabriele Ihorst ²⁰ , Silke Lassmann ⁹ , Philip Keye ²¹ , Susana Minguet ²² , Dirk Schadendorf ²³ , Selma Ugurel ²⁴ , David Rafei-Shamsabadi ²⁵ , Robert Thimme ²⁶ , Peter Hasselblatt ²⁶ , Bertram Bengsch ²⁷ , Christoph Schell ⁹ , Erika L Pearce ²⁸ , Frank Meiss ²⁵ , Burkhard Becher ⁴ , Carolin Funke-Lorenz ²⁴ , Jan-Malte Placke ²⁴ , Petya Apostolova ²⁹ , Robert Zeiser ³⁰

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: [email protected].
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: [email protected].

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.