Abstract B034: Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants
Authors: Or-Yam Revach, Angelina Cicerchia, Ofir Shorer, Boryana Petrova, Seth Anderson, Joshua Park, Chen Lee, Arnav Mehta, Samuel Wright, Niamh McNamee, Aya Tal-Mason, Giulia Cattaneo, Payal Tiwari, Hongyan Xie, Johanna Sweere, Li-Chun Cheng, Natalia Sigal, Elizabeth Enrico, Marisa Miljkovic, Shane Evans, Ngan Nguyen, Mark Whidden, Ramji Srinivasan, Matthew Spitzer, Yi Sun, Tatyana Sharova, Aleigha Lawless, William Michaud, Martin Rasmussen, Jacy Fang, Claire Palin, Feng Chen, Xinhui Wang, Cristina Ferrone, Donald Lawrence, Ryan Sullivan, David Liu, Uma Sachdeva, Debattama Sen, Keith Flaherty, Robert Manguso, Lloyd Bod, Manolis Kellis, Genevieve Boland, Keren Yizhak, Jiekun Yang, Naama Kanarek, Moshe Sade-Feldman, Nir Hacohen, Russell Jenkins
Journal: Cancer Research (2025)

Abstract T cell exhaustion is a major driver of immune checkpoint blockade (ICB) resistance and clinically effective strategies to prevent or reverse T cell exhaustion to restore ICB sensitivity are lacking. CD38, an ecto-enzyme involved in NAD+ catabolism, is highly expressed in exhausted CD8+ T cells in human melanoma, yet its role in T cell exhaustion remains to be elucidated. Here we show that CD38+CD8+ T cells are enriched during tumor progression and following unsuccessful ICB treatment and are strongly associated with ICB resistance in melanoma. Chronic TCR activation and type I interferon stimulation upregulate CD38 in human T cells, leading to mitochondrial dysfunction and reduced anti-tumor activity. Disrupting CD38 restored cellular NAD+ pools and T cell bioenergetics, leading to improved T cell proliferation, enhanced effector function and elevation in T cells “stemness” markers that are associated with increased response to ICB in human melanoma. Importantly, targeting CD38 in a cohort of patient-derived organotypic tumor spheroid (PDOTS), human living tumor explants, with intact immune compartment, demonstrates that CD38-directed therapies can overcome ICB resistance in clinically resistant human melanoma, an effect that is furthered enhanced by supplementation with NAD+. These results emphasize the need for further preclinical and clinical evaluation of CD38 directed therapies in melanoma and underscore the importance of NAD+ as a vital metabolite to enhance those therapies. Citation Format: Or-Yam Revach, Angelina Cicerchia, Ofir Shorer, Boryana Petrova, Seth Anderson, Joshua Park, Chen Lee, Arnav Mehta, Samuel Wright, Niamh McNamee, Aya Tal-Mason, Giulia Cattaneo, Payal Tiwari, Hongyan Xie, Johanna Sweere, Li-Chun Cheng, Natalia Sigal, Elizabeth Enrico, Marisa Miljkovic, Shane Evans, Ngan Nguyen, Mark Whidden, Ramji Srinivasan, Matthew Spitzer, Yi Sun, Tatyana Sharova, Aleigha Lawless, William Michaud, Martin Rasmussen, Jacy Fang, Claire Palin, Feng Chen, Xinhui Wang, Cristina Ferrone, Donald Lawrence, Ryan Sullivan, David Liu, Uma Sachdeva, Debattama Sen, Keith Flaherty, Robert Manguso, Lloyd Bod, Manolis Kellis, Genevieve Boland, Keren Yizhak, Jiekun Yang, Naama Kanarek, Moshe Sade-Feldman, Nir Hacohen, Russell Jenkins. Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B034.