Braun Lukas M, Giesler Sophie, Andrieux Geoffroy, Riemer Roxane, Talvard-Balland Nana, Duquesne Sandra, Rückert Tamina, Unger Susanne, Kreutmair Stefanie, Zwick Melissa, Follo Marie, Hartmann Alina, Osswald Natascha, Melchinger Wolfgang, Chapman Stefanie, Hutchinson James A, Haferkamp Sebastian, Torster Leopold, Kött Julian, Gebhardt Christoffer, Hellwig Dirk, Karantzelis Nikolaos, Wallrabenstein Till, Lowinus Theresa, Yücel Mehtap, Brehm Niklas, Rawluk Justyna, Pfeifer Dietmar, Bronsert Peter, Rogg Manuel, Mattern Sven, Heikenwälder Mathias, Fusco Stefano, Malek Nisar P, Singer Stephan, Schmitt-Graeff Annette, Ceteci Fatih, Greten Florian R, Blazar Bruce R, Boerries Melanie, Köhler Natalie, Duyster Justus, Ihorst Gabriele, Lassmann Silke, Keye Philip, Minguet Susana, Schadendorf Dirk, Ugurel Selma, Rafei-Shamsabadi David, Thimme Robert, Hasselblatt Peter, Bengsch Bertram, Schell Christoph, Pearce Erika L, Meiss Frank, Becher Burkhard, Funke-Lorenz Carolin, Placke Jan-Malte, Apostolova Petya, Zeiser Robert
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.
Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Cancer Cell. 2025 Feb 10;43(2):269-291.e19. doi: 10.1016/j.ccell.2025.01.004.
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 CD4IFN-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.
接受免疫检查点抑制剂（ICI）治疗的癌症患者发生的免疫相关不良事件（irAE）会导致发病，并且需要停止治疗。比较irAE的治疗方法，我们发现，体外光化学疗法（ECP）后小鼠的抗肿瘤免疫力得以保留，但糖皮质激素、肿瘤坏死因子α（TNFα）阻断和α4β7整合素抑制会降低其抗肿瘤免疫力。局部脂联素的产生通过降低结肠中促炎性T细胞频率，同时保留肿瘤特异性T细胞发育，从而产生组织特异性效应。一项针对14例患者的前瞻性1b/2期试验（欧洲临床试验注册号：2021-002073-26）显示，ECP相关毒性较低。所有irAE的总体缓解率为92%（95%置信区间[CI]：63.97%-99.81%）；结肠炎特异性完全缓解率为100%（95%CI：63.06%-100%）。ECP治疗后，所有患者的糖皮质激素剂量均可减少。在ICI诱导的结肠炎患者中，ECP-脂联素轴可降低肠道组织驻留记忆T细胞的活化和CD4IFN-γ T细胞，且没有抗肿瘤免疫力丧失的迹象。总之，我们确定脂联素是一种免疫调节分子，可控制ICI诱导的irAE，而不阻断抗肿瘤免疫力。
