Revach et al. showed that in ICB-treated patients with melanoma or NSCLC, CD8+ TIL expression of CD38, an ecto-enzyme involved in NAD+ catabolism, increased in parallel with co-inhibitory receptor and inversely with Tcf7 expression, and predicted ICB resistance. Cd38 was upregulated in exhausted CD8+ TILs of ICB-treated tumor-bearing mice, and Cd38 deletion reduced chronic stimulation-induced T cell dysfunction. CD38 blockade overcame ICB resistance in mouse- and patient-derived organotypic tumor spheroids. CD38 blockade or deletion reversed metabolic defects in exhausted T cells to allow Tcf7 expression, T cell function, and ICB response.
Contributed by Paula Hochman
ABSTRACT: A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma(1,2). T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance(3). Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD(+)) catabolism, is highly expressed in exhausted CD8(+) T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38(hi)CD8(+) T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD(+) pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD(+) axis in promoting T cell exhaustion and ICB resistance and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.
Author Info: (1) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, M
Author Info: (1) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (2) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (3) Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. (4) Harvard Medical School, Boston, MA, USA. Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (5) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (7) Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA. (8) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (9) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (10) Harvard Medical School, Boston, MA, USA. Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA, USA. (11) Harvard Medical School, Boston, MA, USA. Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA, USA. (12) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (13) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (14) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (15) Teiko Bio, Salt Lake City, UT, USA. (16) Teiko Bio, Salt Lake City, UT, USA. (17) Teiko Bio, Salt Lake City, UT, USA. (18) Teiko Bio, Salt Lake City, UT, USA. (19) Teiko Bio, Salt Lake City, UT, USA. (20) Teiko Bio, Salt Lake City, UT, USA. (21) Teiko Bio, Salt Lake City, UT, USA. (22) Teiko Bio, Salt Lake City, UT, USA. (23) Teiko Bio, Salt Lake City, UT, USA. (24) Teiko Bio, Salt Lake City, UT, USA. Department of Otolaryngology-Head and Neck Cancer, University of California, San Francisco, San Francisco, CA, USA. Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA, USA. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Chan Zuckerberg Biohub, San Francisco, CA 94158; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (25) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (26) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (27) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (28) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (29) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (30) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (31) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (32) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (33) Harvard Medical School, Boston, MA, USA. Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (34) Harvard Medical School, Boston, MA, USA. Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. Department of Surgery, Cedars-Sinai Medical Center Los Angeles, CA, USA. (35) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (36) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (37) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (38) Harvard Medical School, Boston, MA, USA. Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA, USA. (39) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (40) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (41) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (42) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (43) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (44) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (45) Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. (46) Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA. (47) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (48) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (49) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (50) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
