Hypoxia-induced soluble CD137 in malignant cells blocks CD137L-costimulation as an immune escape mechanism
Labiano S (1), Palazón A (1), Bolaños E (1), Azpilikueta A (1), Sánchez-Paulete AR (1), Morales-Kastresana A (1), Quetglas JI (1), Perez-Gracia JL (1), Gúrpide A (1), Rodriguez-Ruiz M (1), Aznar MA (1), Jure-Kunkel M (2), Berraondo P (1), Melero I (1).
(1) CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
(2) Bristol-Myers Squibb Pharmaceutical Research Institute , Princeton, NJ, USA.
Hypoxia is a common feature in solid tumors that has been implicated in immune evasion. Previous studies from our group have shown that hypoxia upregulates the co-stimulatory receptor CD137 on activated T lymphocytes and on vascular endothelial cells.
In this study, we show that exposure of mouse and human tumor cell lines to hypoxic conditions (1% O2) promotes CD137 transcription. However, the resulting mRNA is predominantly an alternatively spliced form that encodes for a soluble variant, lacking 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.
Indeed, silencing CD137 with shRNA renders more immunogenic tumor-cell variants upon inoculation to immunocompetent mice but which readily grafted on immunodeficient or CD8+ T-cell-depleted mice. These mechanisms are interpreted as a molecular strategy deployed by tumors to repress lymphocyte co-stimulation via CD137/CD137L.
CITATION Oncoimmunology. 2015 Jun 24;5(1):e1062967