Immune checkpoint inhibitor (ICI) therapy continues to revolutionize melanoma treatment, but only a subset of patients respond. Major efforts are underway to develop minimally invasive predictive assays of ICI response. Using single-cell transcriptomics, we discovered a unique CD8 T cell blood/tumor-shared subpopulation in melanoma patients with high levels of oxidative phosphorylation (OXPHOS), the ectonucleotidases CD38 and CD39, and both exhaustion and cytotoxicity markers. We called this population with high levels of OXPHOS “CD8+ TOXPHOS cells.” We validated that higher levels of OXPHOS in tumor- and peripheral blood–derived CD8+ TOXPHOS cells correlated with ICI resistance in melanoma patients. We then developed an ICI therapy response predictive model using a transcriptomic profile of CD8+ TOXPHOS cells. This model is capable of discerning responders from nonresponders using either tumor or peripheral blood CD8 T cells with high accuracy in multiple validation cohorts. In sum, CD8+ TOXPHOS cells represent a critical immune population to assess ICI response with the potential to be a new target to improve outcomes in melanoma patients.
A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients
Disclosures: P. Funchain reported grants from Pfizer and Bristol Myers Squibb and personal fees from Eisai outside the submitted work. A. Rodriguez reported non-financial support from Lipid Genomics during the conduct of the study and non-financial support from Lipid Genomics outside the submitted work; in addition, A. Rodriguez had a patent to LAG3 issued (Lipid Genomics). No other disclosures were reported.
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Chuan Li, Yee Peng Phoon, Keaton Karlinsey, Ye F. Tian, Samjhana Thapaliya, Angkana Thongkum, Lili Qu, Alyssa Joyce Matz, Mark Cameron, Cheryl Cameron, Antoine Menoret, Pauline Funchain, Jung-Min Song, C. Marcela Diaz-Montero, Banumathi Tamilselvan, Jackelyn B. Golden, Michael Cartwright, Annabelle Rodriguez, Christopher Bonin, Anthony Vella, Beiyan Zhou, Brian R. Gastman; A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients. J Exp Med 3 January 2022; 219 (1): e20202084. doi: https://doi.org/10.1084/jem.20202084
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