2. Academic Validation
  3. Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants

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

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: rjenkins@mgh.harvard.edu.
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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