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.
Author Info: (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 In
Author Info: (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) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (5) 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. (6) 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. (7) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (8) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (9) Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (10) 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. (11) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (12) Harvard Medical School, Boston, MA 02115, USA; Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (13) Harvard Medical School, Boston, MA 02115, USA; Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (14) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (15) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (16) 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. (17) Teiko Bio, Salt Lake City, UT 84108, USA. (18) Teiko Bio, Salt Lake City, UT 84108, USA. (19) Teiko Bio, Salt Lake City, UT 84108, USA. (20) Teiko Bio, Salt Lake City, UT 84108, USA. (21) Teiko Bio, Salt Lake City, UT 84108, USA. (22) Teiko Bio, Salt Lake City, UT 84108, USA. (23) Teiko Bio, Salt Lake City, UT 84108, USA. (24) Teiko Bio, Salt Lake City, UT 84108, USA. (25) Teiko Bio, Salt Lake City, UT 84108, USA. (26) 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. (27) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. (28) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (29) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (30) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (31) 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. (32) 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. (33) Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA. (34) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (35) Harvard Medical School, Boston, MA 02115, USA; Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (36) 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. (37) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. (38) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. (39) 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. (40) Harvard Medical School, Boston, MA 02115, USA; Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (41) 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. (42) Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. (43) 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. (44) 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. (45) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (46) 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. (47) Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3200003, Israel. (48) Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (49) 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. (50) 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. (51) 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. (52) 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.
