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>