Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants

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

doi:10.1016/j.xcrm.2025.102210

Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants

Cell Rep Med. 2025 Jun 19:102210. doi: 10.1016/j.xcrm.2025.102210. Online ahead of print.

Authors

Or-Yam Revach¹, Angelina M Cicerchia², Ofir Shorer³, Claire A Palin², Boryana Petrova⁴, Seth Anderson⁵, Baolin Liu⁶, Joshua Park⁶, Lee Chen⁷, Arnav Mehta¹, Samuel J Wright⁶, Niamh McNamee⁸, Aya Tal-Mason⁸, Giulia Cattaneo⁹, Payal Tiwari⁶, Hongyan Xie¹, Johanna M Sweere¹⁰, Li-Chun Cheng¹⁰, Natalia Sigal¹⁰, Elizabeth Enrico¹⁰, Marisa Miljkovic¹⁰, Shane A Evans¹⁰, Ngan Nguyen¹⁰, Mark E Whidden¹⁰, Ramji Srinivasan¹⁰, Matthew H Spitzer¹¹, Yi Sun², Tatyana Sharova⁹, Aleigha R Lawless⁹, William A Michaud⁹, Martin Q Rasmussen⁵, Jacy Fang⁵, Jeannette R Brook¹², Feng Chen⁹, Xinhui Wang¹³, Cristina R Ferrone¹⁴, Donald P Lawrence¹⁵, Ryan J Sullivan¹⁵, David Liu¹⁶, Uma M Sachdeva⁸, Debattama R Sen¹, Keith T Flaherty¹⁵, Robert T Manguso¹, Lloyd Bod¹, Manolis Kellis¹⁷, Genevieve M Boland¹⁸, Keren Yizhak³, Jiekun Yang⁷, Naama Kanarek¹⁹, Moshe Sade-Feldman¹, Nir Hacohen¹, Russell W Jenkins²⁰

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.