Kelsey R. Monson^1,2,3*, Robert Ferguson^1,2,3*, Joanna E. Handzlik^1,2,3, Leah Morales^1,2,3, Jiahan Xiong^1,2,3, Vylyny Chat^1,2,3, Sasha Dagayev^1,2,3, Alireza Khodadadi-Jamayran⁴, Danny Simpson^1,2,3, Esther Kazlow^1,2,3, Anabelle Bunis^1,2,3, Chai Sreenivasaiah^1,2,3, Milad Ibrahim^3,5,6, Iryna Voloshyneya^1,3,7, Wouter Ouwerkerk^{8^}, Rosalie M. Luiten^{8^}, Mariaelena Capone^{9^}, Gabriele Madonna^{9^}, Yuting Lu², Yongzhao Shao², Anna Pavlick^{10^}, Michelle Krogsgaard^1,3,7, Janice Mehnart^1,3,5, Hao Tang¹⁰, Sonia Dolfi¹¹, Daniel Tenney¹¹, John B. A. G. Haanen^{12^}, Thomas F. Gajewski^{13,14,15^}, F. Stephen Hodi^{16^}, Keith T. Flaherty^{17^}, Kasey Couts^{18^}, William Robinson^{18^}, Igor Puzanov^{19^}, Marc S. Ernstoff^{20^}, Osama Rahma^{16^}, Michael Postow^{21,22^}, Ryan J. Sullivan^{17^}, Jason J. Luke^{23,24^}, Paolo A. Ascierto^{9^}, Iman Osman^{1,3,5,6^},  Tomas Kirchhoff^{1,2,3^}

¹Perlmutter Cancer Center, NYU Langone Health, New York, USA

²Departments of Population Health and Environmental Medicine, NYU Langone Health, New York, USA

³The Interdisciplinary Melanoma Cooperative Group, NYU Langone Health, New York, USA

⁴Applied Bioinformatics Laboratories, Office of Science and Research, New York University School of Medicine, New York, NY, USA

⁵Department of Medicine, NYU Langone Health, New York, USA

⁶Ronald O. Perelman Department of Dermatology, NYU Langone Health, New York, USA

⁷Department of Pathology, New York University Grossman School of Medicine, New York, NY,

⁸Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Immunology & Infectious Diseases, Cancer Center Amsterdam, The Netherlands

⁹Melanoma Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy

¹⁰Division of Hematology & Medical Oncology, the Cutaneous Oncology Program, Weill Cornell, New York, NY, USA

¹¹Bristol Myers Squibb Corp., Princeton, NJ, USA

¹²Medical Oncology, Antoni van Leeuwenhoek Nederlands Kanker Instituut, Amsterdam, The Netherlands

¹³Department of Pathology, University of Chicago, Chicago, IL, USA

¹⁴Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA

¹⁵Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA

¹⁶Department of Medical Oncology, Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

¹⁷Center for Melanoma, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

¹⁸Department of Medicine, Division of Medical Oncology, University of Colorado, Aurora, Colorado, USA

¹⁹Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA

²⁰ImmunoOncology Branch (IOB), Developmental Therapeutics Program, Cancer Therapy and Diagnosis Division, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA

²¹Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

²²Department of Medicine, Weill Cornell Medical College, New York, NY, USA

²³Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

²⁴UPMC Hillman Cancer Center, Pittsburgh, PA, USA

^{^}Immuno-Oncology Germline Genetics in Melanoma (IO-GEM) Consortium

 *These authors contributed equally to the work.

Corresponding authors: Tomas Kirchhoff, PhD

Abstract

Response to immune checkpoint inhibitors (ICIs) in metastatic melanoma (MM) varies among patients, and current baseline biomarkers predicting treatment outcomes are limited. As mitochondrial (MT) metabolism has emerged as an important regulator of host immune function, we explored the association of host MT genetics (MT-haplogroups; MT-HGs) with ICI efficacy in 1,225 ICI-treated MM patients from the clinical trial CheckMate-067 and an international MM consortium (IO-GEM). We discovered and validated significant associations of MT haplogroup T (HG-T) with resistance to anti-PD1-based ICI (both single-agent and combination) and have shown that HG-T is independent from established tumor predictors. We also found that HG-T patients exhibit a unique NIVO-resistant baseline peripheral CD8⁺ T cell repertoire compared to other MT-HGs, providing the first link between MT inheritance, host immunity, and ICI resistance. The study proposes a new host blood-based biomarker with stand-alone clinical value predicting ICI efficacy, and pointing to a novel ICI-resistance mechanism associated with MT metabolism with clinical relevance in immuno-oncology.