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

Siqi Chen, Jie Fan, Minghui Zhang, Lei Qin, Donye Dominguez, Alan Long, Gaoxiang Wang, Renqiang Ma, Huabin Li, Yi Zhang, Deyu Fang, Jeffrey Sosman and Bin Zhang ()
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Siqi Chen: Northwestern University Feinberg School of Medicine
Jie Fan: Northwestern University Feinberg School of Medicine
Minghui Zhang: The First Affiliated Hospital of Zhengzhou University
Lei Qin: Northwestern University Feinberg School of Medicine
Donye Dominguez: Northwestern University Feinberg School of Medicine
Alan Long: Northwestern University Feinberg School of Medicine
Gaoxiang Wang: Northwestern University Feinberg School of Medicine
Renqiang Ma: Northwestern University Feinberg School of Medicine
Huabin Li: Fudan University
Yi Zhang: The First Affiliated Hospital of Zhengzhou University
Deyu Fang: Northwestern University Feinberg School of Medicine
Jeffrey Sosman: Northwestern University Feinberg School of Medicine
Bin Zhang: Northwestern University Feinberg School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08123-8

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