Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-07-15 Epub Date: 2025-06-27 DOI:10.1016/j.xcrm.2025.102210

Or-Yam Revach, Angelina M Cicerchia, Ofir Shorer, Claire A Palin, Boryana Petrova, Seth Anderson, Baolin Liu, Joshua 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 R Lawless, William A Michaud, Martin Q Rasmussen, Jacy Fang, Jeannette R Brook, 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

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引用次数: 0

Abstract

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 CD38⁺CD8⁺ 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.

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靶向CD38在人肿瘤外植体中克服免疫治疗耐药。

CD38是一种参与NAD+分解代谢的外酶，在耗尽的CD8+ T细胞中高度表达，并已成为通过钝化T细胞衰竭来改善免疫检查点阻断（ICB）反应的一个有吸引力的靶点。然而，CD38在耗竭T细胞中的确切作用和调控，以及CD38导向的治疗策略在人类癌症中的疗效仍未完全确定。在这里，我们证明CD38+CD8+ T细胞可被慢性TCR激活和I型干扰素刺激诱导，并证实它们与人类黑色素瘤中ICB耐药性的关联。破坏CD38可恢复细胞NAD+池，改善T细胞生物能量学和效应功能。靶向CD38可恢复外植黑色素瘤标本中患者来源的器官型肿瘤球体的ICB敏感性。这些结果支持进一步的临床前和临床评估cd38靶向治疗黑色素瘤，并强调了NAD+作为重要代谢物对增强这些治疗的重要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.