Abstract
Abstract CD8 T cell infiltration into tumors is critical for controlling cancer and relies on interactions between homing receptors (HR) on CD8 T cells and ligands on the vasculature. However, the ligands expressed on tumor vasculature, and the receptor interactions required for entry into tumors are incompletely characterized. The HR ligands VCAM-1 and E-selectin were highly expressed on the vasculature of B16-F1 melanomas expressing the strong antigen ovalbumin (B16-OVA) and growing subcutaneously but were significantly decreased compared to inflamed skin vasculature. In contrast, the vasculature of intraperitoneal tumors expressed MadCAM-1, negligible E-selectin, and lower VCAM-1. However, MadCAM-1 was not displayed on the luminal surface. B16-F1 parental tumors lacking a strong antigen, and B16-OVA tumors grown in Rag1KO animals, expressed negligible VCAM-1 and MadCAM-1, suggesting that previously infiltrating activated adaptive immune cells drove their expression. VCAM-1 and CXCL9/10 enabled entry of CD8 T cell effectors expressing α4β1+ integrin and CXCR3 into both subcutaneous and peritoneal tumors, while E-Selectin enabled entry of E-Selectin ligand+ effectors preferentially into subcutaneous tumors. MadCAM-1 did not mediate entry of α4β7+ effectors into peritoneal tumors, in keeping with its lack of luminal expression. Disrupting immunosuppression with checkpoint blockade inhibitors may increase HR ligand expression on tumor vasculature and improve CD8 T cell entry into tumors.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call