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

S Chen, J Fan, M Zhang, L Qin, D Dominguez… - Nature …, 2019 - nature.com
S Chen, J Fan, M Zhang, L Qin, D Dominguez, A Long, G Wang, R Ma, H Li, Y Zhang…
Nature communications, 2019nature.com
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 …
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.
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