Immune signatures predict development of autoimmune toxicity in immune-checkpoint-inhibitor-treated cancer patients

<strong>Immune signatures predict development of autoimmune toxicity in immune-checkpoint-inhibitor-treated cancer patients</strong> Nicolas Gonzalo Nuñez¹*, Fiamma Berner²*, Ekaterina Friebel¹*, Susanne Unger¹, Mette-Triin Purde², Rebekka Niederer^2,3, Maximilian Porsch⁴, Christa Lichtensteiger², Julia Martinez Gomez⁵, Mariaelena Capone⁶, Gabriele Madonna⁶, Lacin Cevhertas^7,8, Teresa Amaral^9,10, Omar Hasan Ali^2,3,5,11, David Bomze²^,¹², Marie-Therese Abdou², Stefan Diem¹³, Paolo Antonio Ascierto⁶, Reinhard Dummer⁵, Christoph Driessen¹³, Mitch Levesque⁵, Willem van de Veen⁷, Markus Jörger¹³, Martin Früh^13,14, Burkhard Becher¹**, Lukas Flatz^2,3,5,13,15** */** these authors contributed equally Affiliations 1. Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland 2. Institute of Immunobiology, Medical Research Center, Kantonsspital St. Gallen, St.Gallen, Switzerland 3. Department of Dermatology, Kantonsspital St. Gallen, St.Gallen, Switzerland 4. Department of Radiology, Kantonsspital St. Gallen, St.Gallen, Switzerland 5. Department of Dermatology, University Hospital Zurich, Zurich, Switzerland 6. Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Napoli, Italy 7. Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland 8. Department of Medical Immunology, Institute of Health Sciences, Bursa Uludag University, Bursa, Turkey 9. Skin Cancer Center, Department of Dermatology, University Hospital Tübingen, Tübingen, Germany 10. iFIT Cluster of Excellence (EXC 2180), University of Tübingen, Tübingen, Germany 11. Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada 12. Sackler Faculty of Medicine, Tel-Aviv University, Israel 13. Department of Oncology, Kantonsspital St. Gallen, St.Gallen, Switzerland 14. Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland 15. Universitäts-Hautklinik, University of Tübingen, Tübingen, Germany Corresponding authors: Burkhard Becher, Prof. Dr. Institute of Experimental Immunology University of Zurich Winterthurerstrasse 190 8057 Zurich, Switzerland Phone: [phone] Email: [e-mail] Lukas Flatz, Prof. M.D. Universitäts-Hautklinik University of Tübingen 72016 Tübingen, Germany Phone: [phone] Email: [e-mail] <strong>Immune checkpoint inhibitors (ICIs) </strong><strong>have emerged as one of the most promising</strong><strong> treatment </strong><strong>options </strong><strong>for melanoma and non-small cell lung cancer (NSCLC</strong><strong>).</strong><strong> While ICIs can induce effective anti-tumour responses, their use is also frequently associated with immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs</strong> <strong>would enable more accurate clinical risk-benefit-analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs</strong><strong>. In this prospective study we used a multiomics approach including unbiased single-cell profiling and serum analysis to characterise the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. We identified predictive immune signatures and early changes during ICI therapy that were significantly associated with the subsequent development of irAEs</strong><strong> and were distinguished from markers of response to ICI therapy.</strong><strong> These biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs.</strong>**免疫特征可预测接受免疫检查点抑制剂治疗的癌症患者自身免疫毒性的发生** Nicolas Gonzalo Nuñez¹*，Fiamma Berner²*，Ekaterina Friebel¹*，Susanne Unger¹，Mette-Triin Purde²，Rebekka Niederer^2,3，Maximilian Porsch⁴，Christa Lichtensteiger²，Julia Martinez Gomez⁵，Mariaelena Capone⁶，Gabriele Madonna⁶，Lacin Cevhertas^7,8，Teresa Amaral^9,10，Omar Hasan Ali^2,3,5,11，David Bomze^2,12，Marie-Therese Abdou²，Stefan Diem¹³，Paolo Antonio Ascierto⁶，Reinhard Dummer⁵，Christoph Driessen¹³，Mitch Levesque⁵，Willem van de Veen⁷，Markus Jörger¹³，Martin Früh^13,14，Burkhard Becher¹**，Lukas Flatz^2,3,5,13,15** * 本文标*的三位作者为共同第一作者 **作者单位** 1. 瑞士苏黎世大学实验免疫学研究所，苏黎世，瑞士 2. 圣加仑州立医院医学研究中心免疫生物学研究所，圣加仑，瑞士 3. 圣加仑州立医院皮肤科，圣加仑，瑞士 4. 圣加仑州立医院放射科，圣加仑，瑞士 5. 苏黎世大学医院皮肤科，苏黎世，瑞士 6. 意大利国家肿瘤研究所-IRCCS-G.帕斯卡尔基金会，那不勒斯，意大利 7. 瑞士过敏与哮喘研究所（Swiss Institute of Allergy and Asthma Research, SIAF），苏黎世大学，达沃斯，瑞士 8. 布尔萨乌鲁达大学健康科学研究所医学免疫学系，布尔萨，土耳其 9. 蒂宾根大学医院皮肤科皮肤癌中心，蒂宾根，德国 10. 蒂宾根大学iFIT卓越集群（EXC 2180），蒂宾根，德国 11. 不列颠哥伦比亚大学生命科学研究所医学遗传学系，温哥华，加拿大 12. 特拉维夫大学萨克勒医学院，以色列 13. 圣加仑州立医院肿瘤科，圣加仑，瑞士 14. 伯尔尼大学医院因塞尔皮塔尔医学肿瘤科，伯尔尼大学，伯尔尼，瑞士 15. 蒂宾根大学大学皮肤科，蒂宾根，德国 **通讯作者** Burkhard Becher 教授，博士 瑞士苏黎世大学实验免疫学研究所 Winterthurerstrasse 190，8057 苏黎世，瑞士 电话：[phone] 邮箱：[e-mail] Lukas Flatz 教授，医学博士 蒂宾根大学大学皮肤科 72016 蒂宾根，德国 电话：[phone] 邮箱：[e-mail] **免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）** 已成为黑色素瘤与非小细胞肺癌（non-small cell lung cancer, NSCLC）最具前景的治疗手段之一。尽管ICIs可诱导有效的抗肿瘤应答，但该类药物的使用也常伴随免疫相关不良事件（immune-related adverse events, irAEs）。筛选可预测患者发生irAEs风险的生物标志物，能够为ICI治疗提供更精准的临床风险-获益分析思路，同时也可揭示支撑治疗成功与irAEs发生的共有或特有机制。本前瞻性研究采用多组学策略，结合无偏倚单细胞分析与血清学检测，对接受ICI治疗前后的黑色素瘤或NSCLC患者的全身免疫微环境进行了表征。本研究鉴定出与ICI治疗期间后续irAEs发生显著相关的预测性免疫特征及早期变化，且该类特征与ICI治疗应答标志物存在显著差异。上述生物标志物可用于预测哪些患者最有可能从ICI治疗中获益，以及哪些患者需要针对irAEs进行强化监测。