Revach Or-Yam, Cicerchia Angelina M, Shorer Ofir, Palin Claire A, Petrova Boryana, Anderson Seth, Liu Baolin, Park Joshua, Chen Lee, Mehta Arnav, Wright Samuel J, McNamee Niamh, Tal-Mason Aya, Cattaneo Giulia, Tiwari Payal, Xie Hongyan, Sweere Johanna M, Cheng Li-Chun, Sigal Natalia, Enrico Elizabeth, Miljkovic Marisa, Evans Shane A, Nguyen Ngan, Whidden Mark E, Srinivasan Ramji, Spitzer Matthew H, Sun Yi, Sharova Tatyana, Lawless Aleigha R, Michaud William A, Rasmussen Martin Q, Fang Jacy, Brook Jeannette R, Chen Feng, Wang Xinhui, Ferrone Cristina R, Lawrence Donald P, Sullivan Ryan J, Liu David, Sachdeva Uma M, Sen Debattama R, Flaherty Keith T, Manguso Robert T, Bod Lloyd, Kellis Manolis, Boland Genevieve M, Yizhak Keren, Yang Jiekun, Kanarek Naama, Sade-Feldman Moshe, Hacohen Nir, Jenkins Russell W
Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Cell Rep Med. 2025 Jul 15;6(7):102210. doi: 10.1016/j.xcrm.2025.102210. Epub 2025 Jun 27.
CD38, an ecto-enzyme involved in NAD catabolism, is highly expressed in exhausted CD8 T cells and has emerged as an attractive target to improve response to immune checkpoint blockade (ICB) by blunting T cell exhaustion. However, the precise role(s) and regulation of CD38 in exhausted T cells and the efficacy of CD38-directed therapeutic strategies in human cancer remain incompletely defined. Here, we show that CD38CD8 T cells are induced by chronic TCR activation and type I interferon stimulation and confirm their association with ICB resistance in human melanoma. Disrupting CD38 restores cellular NAD pools and improves T cell bioenergetics and effector functions. Targeting CD38 restores ICB sensitivity in a cohort of patient-derived organotypic tumor spheroids from explanted melanoma specimens. These results support 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.
CD38是一种参与NAD分解代谢的胞外酶，在耗竭的CD8 T细胞中高度表达，并已成为一个有吸引力的靶点，可通过减轻T细胞耗竭来改善对免疫检查点阻断（ICB）的反应。然而，CD38在耗竭T细胞中的精确作用和调控以及CD38导向治疗策略在人类癌症中的疗效仍未完全明确。在此，我们表明CD38⁺ CD8 T细胞由慢性TCR激活和I型干扰素刺激诱导产生，并证实它们与人类黑色素瘤中的ICB耐药性相关。破坏CD38可恢复细胞内NAD池，并改善T细胞生物能量学和效应功能。在一组来自切除的黑色素瘤标本的患者来源的器官样肿瘤球体中，靶向CD38可恢复ICB敏感性。这些结果支持在黑色素瘤中对CD38导向疗法进行进一步的临床前和临床评估，并强调NAD作为增强这些疗法的重要代谢物的重要性。
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