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  • Open Access

Novel role of platelet endothelial cell adhesion molecule-1 (PECAM-1) in facilitating TGF-beta-mediated inhibition of T cell function

  • 1,
  • 1,
  • 1,
  • 1,
  • 1 and
  • 2
Journal for ImmunoTherapy of Cancer20153 (Suppl 2) :P242

https://doi.org/10.1186/2051-1426-3-S2-P242

  • Published:

Keywords

  • Wild Type Counterpart
  • Proximity Ligation Assay
  • Inject Tumor Cell
  • Platelet Endothelial Cell Adhesion
  • Inhibitory Axis

Transforming Growth Factor β (TGFb) is an immunosuppressive cytokine that inhibits pro-inflammatory functions of T cells, and is a major contributor to abrogating TH1 and cytotoxic T cell activity against tumors. While canonical signal transduction through effector Smads has been well-defined as a requirement for TGFb-mediated inhibition of T cells, essential non-canonical pathways have not, to date, been defined. This abstract describes the identification of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), CD31, as a novel facilitator of non-canonical TGFβ signal transduction in T cells. Subcutaneously injected tumor cells known to require TGFβ-mediated suppression of immunity for clearance grew more slowly in PECAM-1-/- mice relative to wild type counterparts, and T cells isolated from PECAM-1-/- mice demonstrated relative insensitivity to TGFβ-induced inhibition of IFNγ production and proliferation. Similarly, human T cells lacking PECAM-1 expression demonstrated decreased sensitivity to TGFβ in a manner that could be partially restored by re-expression of PECAM-1. Phosphorylation of PECAM-1 on an Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM) and resultant binding of the inhibitory Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) was observed after co-incubation of T cells with TGFβ and anti-CD3, and inducible co-localization of PECAM-1 with the TGFβ receptor complex was identified using co-immunoprecipitation, confocal microscopy and proximity ligation assays. These studies indicate an unexpected role for PECAM-1 in enhancing crucial inhibitory functions of TGFβ in T cells and suggest that targeting of the PECAM-1/TGFβ inhibitory axis represents a novel means to overcome TGFβ-dependent immunosuppression within the tumor microenvironment.

Authors’ Affiliations

(1)
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI, USA
(2)
Medical College of Wisconsin, Milwaukee, WI, USA

Copyright

© Newman et al. 2015

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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