Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants

  • Cell Rep Med. 2025 Jul 15;6(7):102210. doi: 10.1016/j.xcrm.2025.102210.
Or-Yam Revach  1 ,  Angelina M Cicerchia  2 ,  Ofir Shorer  3 ,  Claire A Palin  2 ,  Boryana Petrova  4 ,  Seth Anderson  5 ,  Baolin Liu  6 ,  Joshua Park  6 ,  Lee Chen  7 ,  Arnav Mehta  1 ,  Samuel J Wright  6 ,  Niamh McNamee  8 ,  Aya Tal-Mason  8 ,  Giulia Cattaneo  9 ,  Payal Tiwari  6 ,  Hongyan Xie  1 ,  Johanna M Sweere  10 ,  Li-Chun Cheng  10 ,  Natalia Sigal  10 ,  Elizabeth Enrico  10 ,  Marisa Miljkovic  10 ,  Shane A Evans  10 ,  Ngan Nguyen  10 ,  Mark E Whidden  10 ,  Ramji Srinivasan  10 ,  Matthew H Spitzer  11 ,  Yi Sun  2 ,  Tatyana Sharova  9 ,  Aleigha R Lawless  9 ,  William A Michaud  9 ,  Martin Q Rasmussen  5 ,  Jacy Fang  5 ,  Jeannette R Brook  12 ,  Feng Chen  9 ,  Xinhui Wang  13 ,  Cristina R Ferrone  14 ,  Donald P Lawrence  15 ,  Ryan J Sullivan  15 ,  David Liu  16 ,  Uma M Sachdeva  8 ,  Debattama R Sen  1 ,  Keith T Flaherty  15 ,  Robert T Manguso  1 ,  Lloyd Bod  1 ,  Manolis Kellis  17 ,  Genevieve M Boland  18 ,  Keren Yizhak  3 ,  Jiekun Yang  7 ,  Naama Kanarek  19 ,  Moshe Sade-Feldman  1 ,  Nir Hacohen  1 ,  Russell W Jenkins  20
Affiliations
  • 1. 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.
  • 2. Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 3. Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3200003, Israel.
  • 4. Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA; Medical University of Vienna, 1090 Vienna, Austria.
  • 5. Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 6. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 7. Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 8. Harvard Medical School, Boston, MA 02115, USA; Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 9. Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 10. Teiko Bio, Salt Lake City, UT 84108, USA.
  • 11. Teiko Bio, Salt Lake City, UT 84108, USA; Department of Otolaryngology-Head and Neck Cancer, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
  • 12. Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 13. Harvard Medical School, Boston, MA 02115, USA; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 14. Harvard Medical School, Boston, MA 02115, USA; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 15. Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
  • 16. Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 17. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 18. Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 19. Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 20. 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. Electronic address: [email protected].
PMID: 40578364 DOI: 10.1016/j.xcrm.2025.102210
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.

Keywords
3D microfluidic culture; CD38; NAD(+); PD-1; T cell exhaustion; cytokines; ex vivo; immunotherapy; organotypic tumor spheroids.
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