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Nat Commun. 2019 Jan 11;10(1):150. doi: 10.1038/s41467-018-08123-8.

CD73 expression on effector T cells sustained by TGF-β facilitates tumor resistance to anti-4-1BB/CD137 therapy.

Author information

1
Department of Medicine-Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
2
Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China.
3
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
4
Department of Allergy Center, Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, China.
5
Department of Otolaryngology-Head and Neck Surgery, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, 200031, Shanghai, China.
6
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
7
Department of Medicine-Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. bin.zhang@northwestern.edu.
8
Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China. bin.zhang@northwestern.edu.

Abstract

Agonist antibodies (Ab) directed against costimulatory molecules on the surface of antigen-primed T cells are in various stages of pre-clinical and clinical trials, albeit with limited therapeutic benefit as single agents. The underlying mechanisms of action remain incompletely understood. Here, we demonstrate an inhibitory role of ecto-enzyme CD73 for agonistic anti-4-1BB/CD137 Ab therapy. In particular, anti-4-1BB treatment preferentially drives CD73- effector T cell response for tumor inhibition. Anti-CD73 neutralizing Ab further improves anti-4-1BB therapy associated with enhanced anti-tumor T cell immunity. However, the TGF-β-rich tumor milieu confers resistance to anti-4-1BB therapy by sustaining CD73 expression primarily on infiltrating CD8+ T cells across several tumor models. TGF-β blockade results in downregulation of CD73 expression on infiltrating T cells and sensitizes resistant tumors to agonistic anti-4-1BB therapy. Thus, our findings identify a mechanism of action for more effective clinical targeting of 4-1BB or likely other costimulatory molecules.

PMID:
30635578
PMCID:
PMC6329764
DOI:
10.1038/s41467-018-08123-8
[Indexed for MEDLINE]
Free PMC Article

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