title: Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma.
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.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Lyford-Pike
authors.forename: Shiwen
authors.initials: S
authors.lastname: Peng
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Young
authors.forename: Janis M
authors.initials: JM
authors.lastname: Taube
authors.forename: William H
authors.initials: WH
authors.lastname: Westra
authors.forename: Belinda
authors.initials: B
authors.lastname: Akpeng
authors.forename: Tullia C
authors.initials: TC
authors.lastname: Bruno
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Richmon
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Justin A
authors.initials: JA
authors.lastname: Bishop
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Charles G
authors.initials: CG
authors.lastname: Drake
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Topalian
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Sara I
authors.initials: SI
authors.lastname: Pai
mesh_terms: D060890:B7-H1 Antigen / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000821:virology; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D027383:Papillomaviridae / Q000302:isolation & purification*; D061026:Programmed Cell Death 1 Receptor / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma