Transforming growth factor-β (TGF-β) is an immunosuppressive cytokine that 
inhibits the proinflammatory functions of T cells, and it is a major factor in 
abrogating T cell activity against tumors. Canonical TGF-β signaling results in 
the activation of Smad proteins, which are transcription factors that regulate 
target gene expression. We found that the cell surface molecule platelet 
endothelial cell adhesion molecule-1 (PECAM-1) facilitated noncanonical 
(Smad-independent) TGF-β signaling in T cells. Subcutaneously injected tumor 
cells that are dependent on TGF-β-mediated suppression of immunity for growth 
grew more slowly in PECAM-1(-/-) mice than in their wild-type counterparts. T 
cells isolated from PECAM-1(-/-) mice demonstrated relative insensitivity to the 
TGF-β-dependent inhibition of interferon-γ (IFN-γ) production, granzyme B 
synthesis, and cellular proliferation. Similarly, human T cells lacking PECAM-1 
demonstrated decreased sensitivity to TGF-β in a manner that was partially 
restored by reexpression of PECAM-1. Co-incubation of T cells with TGF-β and a T 
cell-activating antibody resulted in PECAM-1 phosphorylation on an 
immunoreceptor tyrosine-based inhibitory motif (ITIM) and the recruitment of the 
inhibitory Src homology 2 (SH2) domain-containing tyrosine phosphatase-2 
(SHP-2). Such conditions also induced the colocalization of PECAM-1 with the 
TGF-β receptor complex as identified by coimmunoprecipitation, confocal 
microscopy, and proximity ligation assays. These studies indicate a role for 
PECAM-1 in enhancing the inhibitory functions of TGF-β in T cells and suggest 
that therapeutic targeting of the PECAM-1-TGF-β inhibitory axis represents a 
means to overcome TGF-β-dependent immunosuppression within the tumor 
microenvironment.