1. PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPα axis in HPV negative head and neck squamous cell carcinoma
- Author
-
Yu, Guang-Tao, Bu, Lin-Lin, Huang, Cong-Fa, Zhang, Wen-Feng, Chen, Wan-Jun, Gutkind, J Silvio, Kulkarni, Ashok B, and Sun, Zhi-Jun
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Dental/Oral and Craniofacial Disease ,Clinical Research ,Cancer ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Antibodies ,Monoclonal ,Antigens ,Differentiation ,B7-H1 Antigen ,Blotting ,Western ,CD47 Antigen ,Cell Line ,Tumor ,Gene Expression Regulation ,Neoplastic ,Head and Neck Neoplasms ,Humans ,Immunohistochemistry ,Macrophages ,Mice ,Knockout ,Myeloid Cells ,PTEN Phosphohydrolase ,Papillomaviridae ,Programmed Cell Death 1 Receptor ,Protein Serine-Threonine Kinases ,RNA Interference ,Receptor ,Transforming Growth Factor-beta Type I ,Receptors ,Immunologic ,Receptors ,Transforming Growth Factor beta ,Reverse Transcriptase Polymerase Chain Reaction ,Signal Transduction ,HNSCC ,myeloid-derived suppressor cell ,tumor associated macrophagy ,PD-1 ,Protein-Serine-Threonine Kinases ,Antigens ,CD47 ,Antigens ,CD274 ,Oncology and carcinogenesis - 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.
- Published
- 2015