CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade
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Abstract
Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment. In vitro and in vivo studies demonstrate that CD38 inhibits CD8+ T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment. Significance: CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8+ T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated. Cancer Discov; 8(9); 1156–75. ©2018 AACR. See related commentary by Mittal et al., p. 1066. This article is highlighted in the In This Issue feature, p. 1047
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CD38 overexpression is associated with a dysfunctional and exhausted CD8 T population in PD1 blockade-resistant cancers.
“a recent study showed that CD38 overexpression was associated with a dysfunctional and exhausted CD8 T population in PD1 blockade-resistant cancers123,124”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [124]
CD38 is emerging as a key enzyme involved in inflammageing and senescence, which are strongly associated with neurodegenerative diseases.
“CD38 is emerging as a key enzyme involved in inflammageing and senescence45,105,106, which are strongly associated with neurodegenerative diseases124,128,168,169.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [124]
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- Authors
- Chen, L., Diao, L., Yang, Y., Yi, X., Rodriguez, B. L., Li, Y., Villalobos, P. A., Cascone, T., Liu, X., Tan, L., Lorenzi, P. L., Huang, A., Zhao, Q., Peng, D., Fradette, J. J., Peng, D. H., Ungewiss, C., Roybal, J., Tong, P., Oba, J., Skoulidis, F., Peng, W., Carter, B. W., Gay, C. M., Fan, Y., Class, C. A., Zhu, J., Rodriguez-Canales, J., Kawakami, M., Byers, L. A., Woodman, S. E., Papadimitrakopoulou, V. A., Dmitrovsky, E., Wang, J., Ullrich, S. E., Wistuba, I. I., Heymach, J. V., Qin, F. X.-F., & Gibbons, D. L.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Shanghai First People's Hospital (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- 1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 14MedImmune, Gaithersburg, Maryland.
- Corresponding author
- Gibbons, Don L.
- ORCID
- Chen, Limo
- Diao, Lixia
- Yang, Yongbin
- Yi, Xiaohui
- Rodriguez, B. Leticia
- Li, Yanli
- Cascone, Tina
- Liu, Xi
- Tan, Lin
- Lorenzi, Philip L.
- Huang, Anfei
- Zhao, Qiang
- Peng, Di
- Fradette, Jared J.
- Peng, David H.
- Tong, Pan
- Oba, Junna
- Skoulidis, Ferdinandos
- Peng, Weiyi
- Carter, Brett W.
- Gay, Carl M.
- Class, Caleb A.
- Zhu, Jingfen
- Kawakami, Masanori
- Byers, Lauren Averett
- Woodman, Scott E.
- Papadimitrakopoulou, Vassiliki A.
- Dmitrovsky, Ethan
- Wang, Jing
- Wistuba, Ignacio I.
- Heymach, John V.
- Qin, F. Xiao-Feng
- Gibbons, Don L.
- Venue
- Cancer Discovery
- Published
- 2018-09-01
- Volume
- 8
- Issue
- 9
- Pages
- 1156-1175
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6205194
- OpenAlex
- W2884332748
- Cited by
- 462
- References
- 49
- Citations by year
- 2026: 34 · 2025: 54 · 2024: 47 · 2023: 46 · 2022: 78 · 2021: 68 · 2020: 80 · 2019: 45 · 2018: 8
- FWCI
- 18.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons @ Butler University (Butler University) (submittedVersion)
- Funders
- Division of Cancer Prevention, National Cancer Institute (DCP, NCI) (P50CA070907-16A1)
- Guandong Natural Science Foundation (81590765, 2016-I2M-1-005)
- Center for Strategic Scientific Initiatives, National Cancer Institute (CSSI, NCI) (P50CA070907-18)
- Cancer Prevention and Research Institute of Texas (CPRIT) (CPRIT RP150405, CPRIT-MIRA RP160652-P3, CPRIT RP130397)
- Elsa U. Pardee Foundation (FP00001060)
- HHS | NIH | National Cancer Institute (NCI) (CA087546, CA190722)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CD38, PD-1/PD-L1 blockade, immune checkpoint inhibitor resistance, adenosine receptor signaling, CD8+ T cell suppression, tumor microenvironment, all-trans retinoic acid, interferon-beta, T cell infiltration, combination immunotherapy, biomarkers
- MeSH terms
- Antineoplastic Agents, Immunological, Animals, Carcinoma, Non-Small-Cell Lung, Drug Synergism, Humans, Interferon-gamma, Lung Neoplasms, Melanoma, Membrane Glycoproteins, Tretinoin, Signal Transduction, Up-Regulation, Gene Expression Regulation, Neoplastic, Receptors, Purinergic P1, CD8-Positive T-Lymphocytes, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, ADP-ribosyl Cyclase 1, Tumor Microenvironment, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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