Myeloid Cells Are Enriched in Tonsillar Crypts, Providing Insight into the Viral Tropism of Human Papillomavirus

Am J Pathol. 2021 Oct;191(10):1774-1786. doi: 10.1016/j.ajpath.2021.06.012. Epub 2021 Jul 23.


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 viral 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 multiparameter immunofluorescence staining demonstrated that the tonsillar crypts are enriched with myeloid populations that co-express multiple canonical and noncanonical 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alphapapillomavirus / physiology*
  • Antigens, CD / metabolism
  • B7 Antigens / metabolism
  • B7-H1 Antigen / metabolism
  • Cell Adhesion Molecules / metabolism
  • Epithelium / pathology
  • Epithelium / virology
  • Germinal Center / pathology
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / virology
  • Humans
  • Immune Checkpoint Proteins / metabolism
  • Laser Capture Microdissection
  • Monocytes / pathology
  • Myeloid Cells / pathology*
  • Myeloid Cells / virology*
  • Palatine Tonsil / pathology*
  • Palatine Tonsil / virology*
  • Receptors, Virus / metabolism
  • Transcriptome / genetics
  • Viral Tropism / physiology*


  • Antigens, CD
  • B7 Antigens
  • B7-H1 Antigen
  • CD274 protein, human
  • CD66 antigens
  • Cell Adhesion Molecules
  • Immune Checkpoint Proteins
  • Receptors, Virus
  • VSIR protein, human
  • poliovirus receptor