PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPα axis in HPV negative head and neck squamous cell carcinoma

Oncotarget. 2015 Dec 8;6(39):42067-80. doi: 10.18632/oncotarget.5955.

Abstract

Myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) play key roles in the tumor immune suppressive network and tumor progression. However, precise roles of programmed death-1 (PD-1) in immunological functions of MDSCs and TAMs in head and neck squamous cell carcinoma (HNSCC) have not been clearly elucidated. In the present study, we show that PD-1 and PD-L1 levels were significantly higher in human HNSCC specimen than in normal oral mucosa. MDSCs and TAMs were characterized in mice and human HNSCC specimen, correlated well with PD-1 and PD-L1 expression. αPD-1 treatment was well tolerated and significantly reduced tumor growth in the HNSCC mouse model along with significant reduction in MDSCs and TAMs in immune organs and tumors. Molecular analysis suggests a reduction in the CD47/SIRPα pathway by PD-1 blockade, which regulates MDSCs, TAMs, dendritic cell as well as effector T cells. Hence, these data identify that PD-1/PD-L1 axis is significantly increased in human and mouse HNSCC. Adoptive αPD-1 immunotherapy may provide a novel therapeutic approach to modulate the micro- and macro-environment in HNSCC.

Keywords: HNSCC; PD-1; myeloid-derived suppressor cell; tumor associated macrophagy.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism*
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism
  • Blotting, Western
  • CD47 Antigen / genetics
  • CD47 Antigen / metabolism*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism
  • Humans
  • Immunohistochemistry
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice, Knockout
  • Myeloid Cells / drug effects*
  • Myeloid Cells / metabolism
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Papillomaviridae / physiology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • Antibodies, Monoclonal
  • Antigens, Differentiation
  • B7-H1 Antigen
  • CD47 Antigen
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • Receptors, Transforming Growth Factor beta
  • SIRPA protein, human
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • PTEN Phosphohydrolase