title: Hypoxia-induced soluble CD137 in malignant cells blocks CD137L-costimulation as an immune escape mechanism.
abstract: 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.
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Labiano
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: Asis
authors.initials: A
authors.lastname: Palazón
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: Elixabet
authors.initials: E
authors.lastname: Bolaños
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: Arantza
authors.initials: A
authors.lastname: Azpilikueta
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: Alfonso R
authors.initials: AR
authors.lastname: Sánchez-Paulete
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: Aizea
authors.initials: A
authors.lastname: Morales-Kastresana
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: Jose I
authors.initials: JI
authors.lastname: Quetglas
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Perez-Gracia
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Gúrpide
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Rodriguez-Ruiz
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: M Angela
authors.initials: MA
authors.lastname: Aznar
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute , Princeton, NJ, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Jure-Kunkel
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Berraondo
authors.affiliation: CIMA, Clínica Universidad de Navarra, University of Navarra and IDISNA , Pamplona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
keywords: 4-1BB (CD137); Cancer; hypoxia; immunotherapy