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.
Highlights
Head and neck squamous cell carcinoma (HNSCC), with more than 450,000 newly diagnosed cases every year, is the 6th most common cancer worldwide [1]
There was significantly increased immunostaining for programmed death-1 (PD-1)/PD-L1 in human HNSCC (n = 86) as compared with dysplasia (n = 12) and normal oral mucosa (n = 32) (Fig. 1B)
The activation of the co-inhibitory checkpoint molecule PD-1 in T cells and expansion of Myeloid-derived suppressor cells (MDSCs) are considered the major mechanisms for tumor to escape from immune surveillance [20]
Summary
Head and neck squamous cell carcinoma (HNSCC), with more than 450,000 newly diagnosed cases every year, is the 6th most common cancer worldwide [1]. As the oral cavity is the most frequent site (~90%) affected in HNSCC, it impacts highly critical functions of respiration, swallowing food and water as well as speech [2]. HPV-negative HNSCC is usually accompanied by mutations of p53 and loss of expression of PTEN [3, 4]. In recent years significant advances have been made in targeted therapies, HNSCC recurrence, resistance to chemo-radiotherapy and cervical lymph node metastasis persist as the most important factors affecting the poor prognosis of patients, in refractory HPV-negative HNSCC. Identification and characterization of the molecular mechanisms underlying HNSCC initiation and progression are a priori for timely diagnosis and developing effective treatment
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