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Cancer Discov. 2018 Sep;8(9):1156-1175. doi: 10.1158/2159-8290.CD-17-1033. Epub 2018 Jul 16.

CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade.

Author information

1
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Shanghai First People's Hospital, Shanghai, Shanghai, China.
4
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, Shanghai, China.
6
Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
The Proteomics and Metabolomics Core Facility, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing; Suzhou Institute of Systems Medicine, Suzhou, China.
9
Sun Yat-sen University School of Life Sciences, Guangzhou, Guangdong, China.
10
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
11
Department of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas.
12
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
13
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
14
MedImmune, Gaithersburg, Maryland.
15
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. dlgibbon@mdanderson.org.
16
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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. 1066This article is highlighted in the In This Issue feature, p. 1047.

PMID:
30012853
PMCID:
PMC6205194
[Available on 2019-09-01]
DOI:
10.1158/2159-8290.CD-17-1033

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