Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 142, Issue 5, Pages 999-1009Publisher
WILEY
DOI: 10.1002/ijc.31115
Keywords
notch1; head and neck squamous cell carcinoma; knockout mouse; immune checkpoint; myeloid-derived suppressor cell; tumour-associated macrophage; regulatory T cell
Categories
Funding
- National Natural Science Foundation of China [81672668, 81472529, 81472528, 81672667]
- NIH (Division of Intramural Research, NIDCR)
- Ministry of Education of China (program for new century excellent talents in university) [NCET-13-0439]
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Immune evasion is a hallmark feature of cancer, and it plays an important role in tumour initiation and progression. In addition, tumour immune evasion severely hampers the desired antitumour effect in multiple cancers. In this study, we aimed to investigate the role of the Notch pathway in immune evasion in the head and neck squamous cell carcinoma (HNSCC) microenvironment. We first demonstrated that Notch1 signaling was activated in a Tgfbr1/Pten-knockout HNSCC mouse model. Notch signaling inhibition using gamma-secretase inhibitor (GSI-IX, DAPT) decreased tumour burden in the mouse model after prophylactic treatment. In addition, flow cytometry analysis indicated that Notch signaling inhibition reduced the sub-population of myeloid-derived suppressor cells (MDSCs), tumour-associated macrophages (TAMs) and regulatory T cells (Tregs), as well as immune checkpoint molecules (PD1, CTLA4, TIM3 and LAG3), in the circulation and in the tumour. Immunohistochemistry (IHC) of human HNSCC tissues demonstrated that elevation of the Notch1 downstream target HES1 was correlated with MDSC, TAM and Treg markers and with immune checkpoint molecules. These results suggest that modulating the Notch signaling pathway may decrease MDSCs, TAMs, Tregs and immune checkpoint molecules in HNSCC.
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