| First Author | Chen S | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 150 |
| PubMed ID | 30635578 | Mgi Jnum | J:270312 |
| Mgi Id | MGI:6277677 | Doi | 10.1038/s41467-018-08123-8 |
| Citation | Chen S, et al. (2019) CD73 expression on effector T cells sustained by TGF-beta facilitates tumor resistance to anti-4-1BB/CD137 therapy. Nat Commun 10(1):150 |
| abstractText | 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-beta-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-beta 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. |
