Abstract 4058: Hypoxia-induced soluble CD137 in malignant cells blocks CD137L-costimulation as an immune escape mechanism

Hypoxia is a common feature in solid tumors that has been implicated in immune-evasion. In this study, we show that exposure of mouse and human tumor cell lines to hypoxic conditions (1% O2) promotes CD137 transcription. Previous studies from our group have shown that hypoxia up-regulates the co-stimulatory receptor CD137 on activated T lymphocytes and on vascular endothelial cells. However, our results show that the CD137 transcript upregulated under hypoxia in tumor cell lines is predominantly an alternatively spliced form that encodes for a soluble variant, which lacks the transmembrane domain. Accordingly, soluble CD137 (sCD137) is detectable by ELISA in the supernatant of hypoxia-exposed cell lines and in the serum of tumor-bearing mice. sCD137, as secreted by tumor cells, is able to bind to CD137-Ligand (CD137L). Our studies on primed T lymphocytes in co-culture with stable transfectants for CD137L demonstrate that tumor-secreted sCD137 prevents co-stimulation of T lymphocytes. Such an effect results from preventing the interaction of CD137L with the transmembrane forms of CD137 expressed on T lymphocytes undergoing activation. This mechanism is interpreted as a molecular strategy deployed by tumors to repress lymphocyte co-stimulation via CD137/CD137L. Citation Format: Sara Labiano, Asis Palazon, Jose I. Quetglas, Elixabet Bolanos, Arantza Azpilicueta, Aizea Morales-Kastresana, Alfonso Rodriguez, Maria Rodriguez-Ruiz, Alfonso Gurpide, M Angela Aznar, Maria Jure-Kunkel, Ignacio Melero. Hypoxia-induced soluble CD137 in malignant cells blocks CD137L-costimulation as an immune escape mechanism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4058. doi:10.1158/1538-7445.AM2015-4058