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Human Papilloma Virus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) is clinically distinct from HPV-negative HNSCC, and as such requires differential therapeutic approaches. Accumulating evidence indicates a significant linkage between the immune response within the tissue and pathogenesis of HPV-associated HNSCC. To further elucidate immune-related signatures in HPV-associated HNSCC, we performed multiplex histological analysis in de-identified tissue microarray sections including HPV-positive (n = 21), HPV-negative (n = 17), and normal oropharynx (n = 8). Following immunohistochemistry (IHC) for CD45, CD3, CD8, Foxp3, T-bet, GATA-3, RORgT, CD20, CD56, CD68, MHC class II, CSF1R, CD66b, tryptase, CD83, DC-SIGN, PD-1, and PD-L1, the cell intensity per mm2 ratio/composition, localization were quantitatively evaluated. The HPV-status was confirmed by HPV16/18 polymerase chain reaction and IHC for p16INK4a. IHC for p16 or EpCAM were utilized for defining tumor region. Infiltration of T cell populations including CD45+CD3+CD8+ T cells (P < 0.01), CD45+CD3+CD8−Foxp3+ regulatory T cells (P < 0.05) and CD45+CD3+CD8−Foxp3+T-bet+ Th1 cells (P < 0.01), CD45+CD20+CD3−B cells (P < 0.05), CD45+CD68+CD163− macrophages (P < 0.001), and CD45+Tryptase+ mast cells (P < 0.01) was significantly higher in the HPV-positive group than in the HPV-negative group. CD8/CD68 ratio of HPV-positive tumor was higher than that of HPV-negative tumor (P < 0.05), and the highest CD163−CD68+/CD163+CD68+ ratio was observed in the intra-tumor region of HPV-positive tumors. High PD-L1 expression on CD68+CD163+ macrophages and MHC class II+CD83+ dendritic cells was intensively observed in the intra-tumor region of the HPV-positive group while maturation of dendritic cells assessed by CD83/DC-SIGN ratio was significantly higher in the peritumoral stroma than intra-tumor regions (P < 0.05), indicating distinct immune regulatory mechanisms between intra and peritumoral regions. These signatures provide further evidence of anti-tumor immunity against HPV-positive head and neck cancer, and potentially lead to personalized treatment including immunomodulatory therapeutic targets specialized for the HPV/immune status.
This project was supported by Oregon Clinical and Translational Research Institute (OCTRI), grant number (UL1TR000128) from the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH), and OHSU Knight Cancer Institute, grant number P30 CA069533-17. LMC acknowledges support from the NIH/NCI, DOD BCRP Era of Hope Scholar Expansion Award, Susan B. Komen Foundation, Stand Up To Cancer – Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant, and Brenden-Colson Center for Pancreatic Health.