DOI: 10.5281/zenodo.10807766
title: Inherited mitochondrial genetics predicts clinical efficacy of immune checkpoint inhibition therapies in melanoma.

description: Kelsey R. Monson1,2,3*, Robert Ferguson1,2,3*, Joanna E. Handzlik1,2,3, Leah Morales1,2,3, Jiahan Xiong1,2,3, Vylyny Chat1,2,3, Sasha Dagayev1,2,3, Alireza Khodadadi-Jamayran4, Danny Simpson1,2,3, Esther Kazlow1,2,3, Anabelle Bunis1,2,3, Chai Sreenivasaiah1,2,3, Milad Ibrahim3,5,6, Iryna Voloshyneya1,3,7, Wouter Ouwerkerk8^, Rosalie M. Luiten8^, Mariaelena Capone9^, Gabriele Madonna9^, Yuting Lu2, Yongzhao Shao2, Anna Pavlick10^, Michelle Krogsgaard1,3,7, Janice Mehnart1,3,5, Hao Tang10, Sonia Dolfi11, Daniel Tenney11, John B. A. G. Haanen12^, Thomas F. Gajewski13,14,15^, F. Stephen Hodi16^, Keith T. Flaherty17^, Kasey Couts18^, William Robinson18^, Igor Puzanov19^, Marc S. Ernstoff20^, Osama Rahma16^, Michael Postow21,22^, Ryan J. Sullivan17^, Jason J. Luke23,24^, Paolo A. Ascierto9^, Iman Osman1,3,5,6^,  Tomas Kirchhoff1,2,3^

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.