Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants
CD38, an ecto-enzyme involved in NAD<sup>+</sup> catabolism, is highly expressed in exhausted CD8<sup>+</sup> 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<sup>+</sup>CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> as a vital metabolite to enhance those therapies.
Authors
- Arnav Mehta (ORCID: https://orcid.org/0000-0002-0313-2848)
- Boryana Petrova (ORCID: https://orcid.org/0000-0001-9996-9353)
- Keren Yizhak (ORCID: https://orcid.org/0000-0002-4454-796X)
- Ryan J. Sullivan (ORCID: https://orcid.org/0000-0001-5344-6645)
- Genevieve Marie Boland (ORCID: https://orcid.org/0000-0002-7522-6173)
- Matthew H. Spitzer (ORCID: https://orcid.org/0000-0002-5291-3819)
- Lee Chen
- Samuel J. Wright (ORCID: https://orcid.org/0009-0006-4892-5338)
- Mark Whidden
- Keith T. Flaherty (ORCID: https://orcid.org/0000-0002-3402-0478)
- Uma M. Sachdeva (ORCID: https://orcid.org/0000-0002-0442-3794)
- Joshua Park (ORCID: https://orcid.org/0000-0002-1958-6764)
- Tatyana Sharova (ORCID: https://orcid.org/0000-0003-2123-3906)
- Hongyan Xie (ORCID: https://orcid.org/0000-0002-0153-9986)
- Russell W. Jenkins (ORCID: https://orcid.org/0000-0001-6110-2148)
- Ngan Luu-Thuy Nguyen (ORCID: https://orcid.org/0000-0003-3931-849X)
- Naama Kanarek (ORCID: https://orcid.org/0000-0002-2068-3908)
- Payal Tiwari
- Jacy Fang (ORCID: https://orcid.org/0009-0006-6937-6868)
- Nir Hacohen (ORCID: https://orcid.org/0000-0002-2349-2656)
- Giulia Cattaneo (ORCID: https://orcid.org/0000-0002-7053-3238)
- Donald P. Lawrence (ORCID: https://orcid.org/0000-0001-5288-9110)
- Elizabeth Enrico
- Or‐Yam Revach (ORCID: https://orcid.org/0000-0002-1606-7467)
- Ofir Shorer (ORCID: https://orcid.org/0009-0009-5978-9580)
- Debattama R. Sen (ORCID: https://orcid.org/0000-0002-0947-8284)
- Jiekun Yang (ORCID: https://orcid.org/0000-0003-0920-052X)
- Shane A. Evans
- Seth Anderson (ORCID: https://orcid.org/0000-0003-2419-0585)
- Natalia Sigal (ORCID: https://orcid.org/0000-0003-2831-7053)
- Moshe Sade-Feldman (ORCID: https://orcid.org/0000-0002-0022-0287)
- Niamh McNamee (ORCID: https://orcid.org/0000-0001-6812-3339)
- Angelina M. Cicerchia (ORCID: https://orcid.org/0000-0002-0510-2298)
- Johanna M. Sweere (ORCID: https://orcid.org/0000-0002-9602-8117)
- Yi Sun (ORCID: https://orcid.org/0009-0003-1720-8844)
- Martin Q. Rasmussen (ORCID: https://orcid.org/0009-0001-6655-1257)
- Robert T. Manguso (ORCID: https://orcid.org/0000-0003-1336-413X)
- Aleigha Lawless (ORCID: https://orcid.org/0009-0009-3861-3164)
- Manolis Kellis (ORCID: https://orcid.org/0000-0001-7113-9630)
- William A. Michaud (ORCID: https://orcid.org/0000-0002-3664-2094)
- Aya Tal-Mason
- Claire A. Palin
- Feng Chen (ORCID: https://orcid.org/0000-0002-2699-7190)
- Xinhui Wang (ORCID: https://orcid.org/0000-0003-3674-3685)
- Baolin Liu (ORCID: https://orcid.org/0000-0001-8466-3837)
- David Liu (ORCID: https://orcid.org/0000-0003-0346-5033)
- Jeannette R. Brook (ORCID: https://orcid.org/0009-0004-5605-2691)
- Lloyd Bod (ORCID: https://orcid.org/0000-0001-8124-0863)
- Cristina R. Ferrone
- Marisa Miljkovic
- Ramji Srinivasan
- Li-Chun Cheng
Institutions
- Broad Institute (US)
- Cedars-Sinai Medical Center (US)
- Boston Children's Hospital (US)
- Cancer Research Institute (US)
- Technion – Israel Institute of Technology (IL)
- Massachusetts General Hospital (US)
- Parker Institute for Cancer Immunotherapy (US)
- Rappaport Family Institute for Research in the Medical Sciences (IL)
- Dana-Farber Cancer Institute (US)
- Center for Cancer Research (US)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- Massachusetts Institute of Technology (US)
- Biotronik (Switzerland) (CH)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102210
- Citations
- 7
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 5.58
Funders
- U.S. Department of Defense
- V Foundation for Cancer Research
- National Institutes of Health
- National Cancer Institute