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

被引:0
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作者
Braun, Lukas M. [1 ,2 ]
Giesler, Sophie [1 ]
Andrieux, Geoffroy [3 ]
Riemer, Roxane [1 ]
Talvard-Balland, Nana [1 ]
Duquesne, Sandra [1 ]
Rueckert, Tamina [1 ,2 ]
Unger, Susanne [4 ]
Kreutmair, Stefanie [1 ,4 ]
Zwick, Melissa [1 ,2 ]
Follo, Marie [1 ]
Hartmann, Alina [1 ]
Osswald, Natascha [1 ]
Melchinger, Wolfgang [1 ]
Chapman, Stefanie
Hutchinson, James A. [5 ]
Haferkamp, Sebastian [6 ]
Torster, Leopold [7 ]
Koett, Julian [7 ]
Gebhardt, Christoffer [7 ]
Hellwig, Dirk [8 ]
Karantzelis, Nikolaos [1 ]
Wallrabenstein, Till [1 ]
Lowinus, Theresa [1 ]
Yuecel, Mehtap [1 ]
Brehm, Niklas [1 ]
Rawluk, Justyna [1 ]
Pfeifer, Dietmar [1 ]
Bronsert, Peter [9 ]
Rogg, Manuel [9 ]
Mattern, Sven [10 ]
Heikenwaelder, Mathias
Fusco, Stefano [12 ]
Malek, Nisar P. [12 ]
Singer, Stephan [10 ,11 ]
Schmitt-Graeff, Annette [13 ]
Ceteci, Fatih [14 ]
Greten, Florian R. [14 ]
Blazar, Bruce R. [15 ]
Boerries, Melanie [3 ,16 ]
Koehler, Natalie [1 ]
Duyster, Justus [1 ,16 ]
Ihorst, Gabriele [17 ]
Lassmann, Silke [9 ]
Keye, Philip [18 ]
Minguet, Susana [19 ]
Schadendorf, Dirk [20 ,21 ,22 ]
Ugurel, Selma [20 ,21 ]
Rafei-Shamsabadi, David [23 ]
Thimme, Robert [24 ]
机构
[1] Univ Freiburg, Dept Internal Med 1, Med Ctr Univ Freiburg, Dept Neuroradiol, Freiburg, Germany
[2] Univ Freiburg, Fac Biol, Freiburg, Germany
[3] Univ Freiburg, Inst Med Bioinformat & Syst Med, Med Ctr, Fac Med, Freiburg, Germany
[4] Univ Zurich, Inst Expt Immunol, Zurich, Switzerland
[5] Univ Hosp Regensburg, Dept Surg, Regensburg, Germany
[6] Univ Hosp Regensburg, Dept Dermatol, Regensburg, Germany
[7] Univ Med Ctr Hamburg Eppendorf, Dept Dermatol & Venereol, Hamburg, Germany
[8] Univ Hosp Regensburg, Dept Nucl Med, Regensburg, Germany
[9] Univ Freiburg, Inst Surg Pathol, Fac Med, Med Ctr, Freiburg, Germany
[10] Univ Klinikum, Inst Pathol, D-72076 Tubingen, Germany
[11] Cluster Excellence, Cluster Excellence iFIT EXC Image Guided & Functio, D-72076 Tubingen, Germany
[12] Uniklin Tubingen, Med Klin I, D-38126 Braunschweig, Germany
[13] Univ Freiburg, Freiburg, Germany
[14] Georg Speyer Haus, Inst Tumor Biol & Expt Therapy, Frankfurt, Germany
[15] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplant & Cellular Therapy, Minneapolis, MN USA
[16] Univ Freiburg, Partnership DKFZ & Med Ctr, German Canc Consortium DKTK, Partner Site Freiburg, Freiburg, Germany
[17] Univ Freiburg, Med Ctr, Fac Med, Clin Trials Unit, Freiburg, Germany
[18] Univ Freiburg, Fac Med, Eye Ctr, Med Ctr, Freiburg, Germany
[19] Univ Freiburg, Signalling Res Ctr BIOSS, Freiburg, Germany
[20] Univ Duisburg Essen, Univ Hosp Essen, Dept Dermatol, Essen, Germany
[21] German Canc Consortium DKTK, Partner Site Essen Duesseldorf, Essen, Germany
[22] Univ Duisburg Essen, Natl Ctr Tumor Dis NCT West, Res Ctr One Hlth, Campus Essen & Res Alliance Ruhr, Essen, Germany
[23] Univ Freiburg, Fac Med, Med Ctr, Dept Dermatol, Freiburg, Germany
[24] Univ Freiburg, Dept Internal Med 2, Med Ctr Univ Freiburg, Dept Neuroradiol, Freiburg, Germany
[25] Univ Freiburg, Signalling Res Ctr BIOSS, Freiburg, Germany
[26] Univ Freiburg, CIBSS Ctr Integrat Biol Signalling Studies, Freiburg, Germany
[27] Johns Hopkins Sch Med, Bloomberg Kimmel Inst Canc Immunotherapy, Dept Oncol, Baltimore, MD 21287 USA
[28] Univ Hosp Basel, Fac Med, Dept Biomed, Basel, Switzerland
[29] Univ Basel, Basel, Switzerland
[30] Univ Hosp Basel, Div Hematol, Basel, Switzerland
关键词
VERSUS-HOST-DISEASE; EXTRACORPOREAL PHOTOPHERESIS; MACROPHAGE POLARIZATION; INDUCED COLITIS; ADVERSE EVENTS; TNF-ALPHA; CELLS; IPILIMUMAB; MELANOMA; CANCER;
D O I
10.1016/j.ccell.2025.01.004
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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, TNFa blockade, and a4b7-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 ECPrelated 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-g+ 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.
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页数:43
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