Abstract
Abstract Agonist antibodies (Ab) directed against costimulatory molecule CD137 (4-1BB) on the surface of antigen-primed T-lymphocytes are currently in various stages of pre-clinical and clinical development in advanced ovarian cancers, though therapeutic benefit has been limited as single agents. Here, we identified a novel mechanism of tumor-reactive CD8+ T cell unresponsiveness in ovarian cancer driven by the upregulation of CD73 (ecto-5′-nucleotidase), which prevents CD8+ T cell activity from engagement of the CD137 costimulatory molecule. Accordingly, CD73-deificient mice treated with anti-CD137 Ab survived significantly longer wild-type mice against an ovarian tumor challenge. To explore the therapeutic relevance of these observations, we combined anti-CD137 and anti-CD73 Ab to treat mice with established ovarian cancers. This combination therapy induced tumor regression associated with enhanced antitumor CD8+ T cell responses and reduced CD4+Foxp3+ regulatory T cells number and function. Mechanistically, CD137 engagement-triggered antitumor T cell activity was diminished in response to microenvironmental transforming growth factor-β (TGF-β) that was essential for CD73 induction. Furthermore, extracellular adenosine generation by CD73 abrogated T cell activity through A2BR activation in the face of agonistic anti-CD137 treatment. Our study demonstrates that CD73 blockade has critical implications for effective clinical targeting of CD137 and possibly other costimulatory molecules. Note: This abstract was not presented at the conference. Citation Format: Siqi Chen, Jie Fan, Donye Dominguez, Qin Lei, Alan Long, Deyu Fang, Bin Zhang. CD73 BLOCKADE OVERCOMES RESISTANCE TO AGONISTIC ANTI-CD137 ANTIBODY THERAPY IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-117.
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