Differential Expression of Homing Receptor Ligands on Tumor-Associated Vasculature that Control CD8 Effector T-cell Entry

• Published in: Cancer immunology research 2017-12, Vol.5 (12), p.1062-1073
• Main Authors: Woods, Amber N, Wilson, Ashley L, Srivinisan, Nithya, Zeng, Jianhao, Dutta, Arun B, Peske, J David, Tewalt, Eric F, Gregg, Randal K, Ferguson, Andrew R, Engelhard, Victor H
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Animals; Biomarkers; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Chemokine CXCL9 - genetics; E-Selectin - genetics; E-Selectin - metabolism; Gene Expression Regulation, Neoplastic; Integrin alpha4beta1 - genetics; Ligands; Melanoma, Experimental; Mice; Models, Biological; Neoplasms - etiology; Neoplasms - pathology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - immunology; Receptors, Lymphocyte Homing - metabolism; Vascular Cell Adhesion Molecule-1 - genetics
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-17-0190

Although CD8 T cells are critical for controlling tumors, how they are recruited and home to primary and metastatic lesions is incompletely understood. We characterized the homing receptor (HR) ligands on tumor vasculature to determine what drives their expression and their role in T-cell entry. The anatomic location of B16-OVA tumors affected the expression of E-selectin, MadCAM-1, and VCAM-1, whereas the HR ligands CXCL9 and ICAM-1 were expressed on the vasculature regardless of location. VCAM-1 and CXCL9 expression was induced by IFNγ-secreting adaptive immune cells. VCAM-1 and CXCL9/10 enabled CD8 T-cell effectors expressing α β integrin and CXCR3 to enter both subcutaneous and peritoneal tumors, whereas E-selectin enabled E-selectin ligand effectors to enter subcutaneous tumors. However, MadCAM-1 did not mediate α β effector entry into peritoneal tumors due to an unexpected lack of luminal expression. These data establish the relative importance of certain HRs expressed on activated effectors and certain HR ligands expressed on tumor vasculature in the effective immune control of tumors. .