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
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology*
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism*
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B7-H1 Antigen / antagonists & inhibitors
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B7-H1 Antigen / genetics
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B7-H1 Antigen / metabolism
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Blotting, Western
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CD47 Antigen / genetics
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CD47 Antigen / metabolism*
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Cell Line, Tumor
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Gene Expression Regulation, Neoplastic / drug effects
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Head and Neck Neoplasms / drug therapy*
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Head and Neck Neoplasms / genetics
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Head and Neck Neoplasms / metabolism
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Humans
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Immunohistochemistry
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Macrophages / drug effects
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Macrophages / metabolism
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Mice, Knockout
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Myeloid Cells / drug effects*
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Myeloid Cells / metabolism
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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Papillomaviridae / physiology
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Programmed Cell Death 1 Receptor / antagonists & inhibitors*
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Programmed Cell Death 1 Receptor / genetics
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Programmed Cell Death 1 Receptor / immunology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA Interference
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism*
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Signal Transduction / genetics
Substances
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Antibodies, Monoclonal
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Antigens, Differentiation
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B7-H1 Antigen
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CD47 Antigen
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Programmed Cell Death 1 Receptor
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Receptors, Immunologic
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Receptors, Transforming Growth Factor beta
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SIRPA protein, human
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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PTEN Phosphohydrolase