γ-Secretase inhibitor reduces immunosuppressive cells and enhances tumour immunity in head and neck squamous cell carcinoma.
Int J Cancer
; 142(5): 999-1009, 2018 03 01.
Article
en En
| MEDLINE
| ID: mdl-29047105
ABSTRACT
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 a γ-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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Tiazoles
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Carcinoma de Células Escamosas
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Linfocitos T Reguladores
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Células Mieloides
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Diaminas
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Modelos Animales de Enfermedad
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Secretasas de la Proteína Precursora del Amiloide
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Neoplasias de Cabeza y Cuello
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Int J Cancer
Año:
2018
Tipo del documento:
Article