Or-Yam Revach, Angelina M Cicerchia, Ofir Shorer, Boryana Petrova, Seth Anderson, Josh Park, Lee Chen, Arnav Mehta, Samuel J Wright, Niamh McNamee, Aya Tal-Mason, Giulia Cattaneo, Payal Tiwari, Hongyan Xie, Johanna M Sweere, Li-Chun Cheng, Natalia Sigal, Elizabeth Enrico, Marisa Miljkovic, Shane A Evans, Ngan Nguyen, Mark E Whidden, Ramji Srinivasan, Matthew H Spitzer, Yi Sun, Tatyana Sharova, Aleigha Lawless, William A Michaud, Martin Q Rasmussen, Jacy Fang, Claire Palin, Feng Chen, Xinhui Wang, Cristina R Ferrone, Donald P Lawrence, Ryan J Sullivan, David Liu, Uma M Sachdeva, Debattama R Sen, Keith T Flaherty, Robert T Manguso, Lloyd Bod, Manolis Kellis, Genevieve M Boland, Keren Yizhak, Jiekun Yang, Naama Kanarek, Moshe Sade-Feldman, Nir Hacohen, Russell W Jenkins
A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics...
February 17, 2024: bioRxiv