PD-1:PD-L1(B7-H1) pathway in adaptive resistance: A novel mechanism for tumor immune escape in human papillomavirus-related head and neck cancers.

Abstract

5506 Background: Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) are associated with a strong host immune response. Despite ample tumor infiltrating lymphocytes (TILs), the cancer is able to persist and grow. Here, we provide evidence for an adaptive immune resistance mechanism mediated through the PD-1:PD-L1 pathway. Methods: We evaluated the peripheral blood and tumor infiltrating lymphocytes for PD-1 expression using flow cytometry in HPV-HNSCC patients. We evaluted PD-L1 expression within the tumors using immunohistochemistry. We performed functional assays evaluating IFN-gamma secretion of PD-1+ and PD-1(-) CD8+ T cells isolated from the tumor microenvironment of PD-L1+ and PD-L1(-) HPV-related head and neck cancers. Results: We found the majority of CD8+ TILs in HPV-HNSCC express the PD-1 co-inhibitory receptor. We report a striking association between expression of its ligand PD-L1 on tumor cells and tumor associated macrophages, and the presence of TILs. Interestingly, membranous PD-L1 staining on tumor cells and CD68+ antigen presenting cells was geographically localized to the periphery of tumor nests and juxtaposed to fronts of infiltrating T cells. Functional assays demonstrated that PD-1-dependent T cell inhibition required expression of PD-L1 in the tumor microenvironment. Finally, we report localized expression of PD-L1 in the deep crypts of normal tonsils, the site of HPV infection and origin of HPV-HNSCC. Conclusions: Our findings support the role of the PD-1:PD-L1 interaction in creating an immune-privileged site for initial viral infection and subsequently adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC.