Tumor Endothelial Cell-Mediated Antigen-Specific T-cell Suppression via the PD-1/PD-L1 Pathway

Tumor endothelial cells (TEC) play multiple roles in the regional specialization of vascular structure and physiology. Because TECs in the tumor microenvironment come in contact with circulating immune cells, they might influence not only trafficking but also the antitumor cellular immune response. In a mouse tumor implantation model with B16 melanoma cells, TECs expressed MHC class II, costimulating molecules, and programmed death-ligand 1 (PD-L1), suggesting that they are antigen (Ag)-presenting cells with suppressive activity. Furthermore, TECs were able to take up and present tumor-derived ovalbumin (OVA) peptide on MHC class I molecules. In functional assays, B16-OVA tumor-derived TECs significantly suppressed the proliferation and Ag-specific cytotoxicity of OVA-specific CD8⁺ T cells relative to those of B16 tumor-derived TECs. This suppressive activity required cell-cell contact and was abrogated by PD-L1 blockade. TECs impaired proinflammatory cytokine production of CD8⁺ T cells, including IL2, TNFα, and IFNγ. B16-OVA tumor-derived TECs induced immunosuppressive CD4⁺ T cells that suppressed OVA-specific CD8⁺ T-cell proliferation via inhibitory cytokines, including IL10 and TGFβ. Deficiency of PD-L1 in TECs, but not in hematopoietic cells, impaired suppression and apoptosis of tumor-infiltrating CD8⁺ T cells, resulting in inhibition of tumor development in vivo model. These data suggest that TECs might regulate the immune response of tumor Ag-specific CD8⁺ T cells via the PD-1/PD-L1 pathway and induce immune suppressive CD4⁺ T cells in an Ag-specific manner, contributing to tumor immune evasion. IMPLICATIONS: The findings of this study might encourage the further development of novel anticancer therapies and strategies.