TY - JOUR
T1 - A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients
AU - Li, Chuan
AU - Phoon, Yee Peng
AU - Karlinsey, Keaton
AU - Tian, Ye F.
AU - Thapaliya, Samjhana
AU - Thongkum, Angkana
AU - Qu, Lili
AU - Matz, Alyssa Joyce
AU - Cameron, Mark
AU - Cameron, Cheryl
AU - Menoret, Antoine
AU - Funchain, Pauline
AU - Song, Jung Min
AU - Diaz-Montero, C. Marcela
AU - Tamilselvan, Banumathi
AU - Golden, Jackelyn B.
AU - Cartwright, Michael
AU - Rodriguez, Annabelle
AU - Bonin, Christopher
AU - Vella, Anthony
AU - Zhou, Beiyan
AU - Gastman, Brian R.
N1 - Publisher Copyright:
© 2021 Li et al.
PY - 2021/11/22
Y1 - 2021/11/22
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20202084
DO - 10.1084/jem.20202084
M3 - Article
C2 - 34807232
AN - SCOPUS:85122052195
SN - 0022-1007
VL - 219
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
M1 - e20202084
ER -