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Myeloid cells are enriched in tonsillar crypts providing insight into the host tropism of HPV

ABSTRACT: Viruses are the second leading cause of cancer worldwide, and human papillomavirus (HPV)-associated head and neck cancers are increasing in incidence in the United States. HPV preferentially infects the crypts of the tonsils rather than the surface epithelium. The present study sought to characterize the unique microenvironment within the crypts to better understand the host tropism of HPV to a lymphoid rich organ. Laser-capture microdissection of distinct anatomic areas (crypts, surface epithelium, and germinal centers) of the tonsil coupled with transcriptional analysis and multi-parameter immunofluorescence staining was performed and demonstrated that the tonsillar crypts are enriched with myeloid populations which co-express multiple canonical and non-canonical immune checkpoints, including PD-L1, CTLA-4, HAVCR2 (TIM-3), ADORA2A, IDO1, BTLA, LGALS3, CDH1, CEACAM1, PVR, and C10orf54 (VISTA). The resident monocytes may foster a permissive microenvironment that facilitates HPV infection and persistence. Furthermore, the myeloid populations within HPV-associated tonsil cancers co-express the same immune checkpoints, providing insight into potential novel immunotherapeutic targets for HPV-associated head and neck cancers. The associated paper "Myeloid cells are enriched in tonsillar crypts providing insight into the host tropism of HPV", Austin K. Mattox, Jessica Roelands, Talia Saal, Yang Cheng, Darawan Rinchai, Wouter Hendrickx, Geoffrey D. Young, Thomas J. Diefenbach, Alan E. Berger, William H. Westra, Justin A. Bishop, William C. Faquin, Francesco M. Marincola, Mikael J. Pittet, Davide Bedognetti, and Sara I. Pai; The American Journal of Pathology, Online ahead of print DOI:https://doi.org/10.1016/j.ajpath.2021.06.012

ORGANISM(S): Homo sapiens

PROVIDER: GSE155139 | GEO | 2021/06/18

REPOSITORIES: GEO

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Project description:Head and neck cancer (HNC) is the fifth most common malignancy worldwide with an annual mortality rate of 200,000. About 90% of HNC can be classified as head and neck squamous cell carcinomas (HNSCC), of which approximately 75% are attributed to alcohol and tobacco consumption and 25 are associated with human papillomavirus (HPV), predominantly HPV16. HPV-associated OPC have better prognosis and a more favorable response to therapy as compared to HPV-negative tumors. Viral oncoproteins are capable of transforming primary human keratinocytes from either genital or oral epithelia in vitro and most likely play the same role in vivo, by disrupting cell-cycle regulatory pathways leading to a genetic progression to ano-genital cancer and OPC. However, the precise mechanisms by which HPV mediates malignant transformation of keratinocytes in the upper digestive tract epithelia are not entirely clear. HPV E7-mediated inactivation of pRb results in overexpression of p16INK4A, which is commonly used as a clinical surrogate marker for HPV positivity/activity. However, high p16INK4A alone has insufficient sensitivity and specificity as a biomarker of HPV positivity in different mucosal sub-sites of HNC. Therefore, increasing emphasis is being placed on the assessment of viral load and E7 oncogene expression, resulting in further classification of HPV positive OPC as HPV-active and HPV-inactive. Differences in risk factors, age of presentation, clinical behavior and gene expression profiles indicate that HPV-positive and HPV-negative tumors develop via different molecular mechanisms and are biologically distinct. This study aimed to compare the gene expression profiles of HPV-active OPCs and normal benign uvula/tonsil tissues and determine what biological processes and pathways are affected in HPV-active tumors. ANALYSIS 5: Two-condition, one-color experiment: HPV-active oropharyngeal tumor samples and normal benign uvula/tonsil tissues. Biological replicates: 12 HPV active samples and 4 Normal samples.

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Myeloid cells are enriched in tonsillar crypts providing insight into the host tropism of HPV

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