Evidence for a Role of the PD-1:PD-L1 Pathway in Immune Resistance of HPV-Associated Head and Neck Squamous Cell Carcinoma

TLDR

Human papillomavirus‑associated head and neck squamous cell carcinomas arise in the tonsils, a key immune organ, yet the virus evades immune elimination during malignant transformation and progression. The study aims to provide evidence for the role of the PD‑1:PD‑L1 pathway in HPV‑HNSCC immune resistance. We found that PD‑L1 is expressed on tumor cells and macrophages at lymphocyte fronts, CD8⁺ tumor‑infiltrating lymphocytes express high PD‑1, and IFN‑γ mRNA is elevated in PD‑L1⁺ tumors, supporting a role for PD‑1:PD‑L1 in creating an immune‑privileged site and adaptive resistance and suggesting therapeutic blockade.

Abstract

Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) originate in the tonsils, the major lymphoid organ that orchestrates immunity to oral infections. Despite its location, the virus escapes immune elimination during malignant transformation and progression. Here, we provide evidence for the role of the PD-1:PD-L1 pathway in HPV-HNSCC immune resistance. We show membranous expression of PD-L1 in the tonsillar crypts, the site of initial HPV infection. In HPV-HNSCCs that are highly infiltrated with lymphocytes, PD-L1 expression on both tumor cells and CD68+ tumor-associated macrophages is geographically localized to sites of lymphocyte fronts, whereas the majority of CD8+ tumor-infiltrating lymphocytes express high levels of PD-1, the inhibitory PD-L1 receptor. Significant levels of mRNA for IFN-γ, a major cytokine inducer of PD-L1 expression, were found in HPV+ PD-L1(+) tumors. Our findings support the role of the PD-1:PD-L1 interaction in creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC.