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

  • Sara Labiano1,
  • Asis Palazon1,
  • Elixabet Bolaños-Mateo1,
  • Arantza Azpilicueta1,
  • Alfonso Rodriguez1,
  • Aizea Morales-Kastresana1,
  • Elena Marin1,
  • Alfonso Gurpide2,
  • Maria Rodriguez-Ruiz1,
  • M Angela Aznar1,
  • Maria Jure-Kunkel3 and
  • Ignacio Melero1
Journal for ImmunoTherapy of Cancer20142(Suppl 3):P218

https://doi.org/10.1186/2051-1426-2-S3-P218

Published: 6 November 2014

Keywords

Tumor Cell LineTransmembrane DomainHypoxic ConditionVascular Endothelial CellHuman Tumor Cell

Hypoxia is a common feature in solid tumors that has been implicated in immune-evasion. 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. 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. This mechanism is interpreted as a molecular strategy deployed by tumors to repress lymphocyte co-stimulation via CD137/CD137L.

Authors’ Affiliations

(1)
Immunology and Immunotherapy, Center for Applied Medical Research, Pamplona, Spain
(2)
Oncology, CUN, Pamplona, Spain
(3)
Oncology Drug Discovery division, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, USA

Copyright

© Labiano et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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