γ‐Secretase inhibitor reduces immunosuppressive cells and enhances tumour immunity in head and neck squamous cell carcinoma

• Published in: International journal of cancer 2018-03, Vol.142 (5), p.999-1009
• Main Authors: Mao, Liang, Zhao, Zhi‐Li, Yu, Guang‐Tao, Wu, Lei, Deng, Wei‐Wei, Li, Yi‐Cun, Liu, Jian‐Feng, Bu, Lin‐Lin, Liu, Bing, Kulkarni, Ashok B., Zhang, Wen‐Feng, Zhang, Lu, Sun, Zhi‐Jun
• Format: Article
• Language: English
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Apoptosis; Cancer; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Proliferation; CTLA-4 protein; Diamines - pharmacology; Disease Models, Animal; Flow cytometry; Head & neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - immunology; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; head and neck squamous cell carcinoma; Humans; Immune checkpoint; Immunohistochemistry; Immunoregulation; Immunosuppression; Inhibition; Kinases; knockout mouse; Lymphocytes; Lymphocytes T; Macrophages; Medical research; Mice; Mice, Knockout; Myeloid Cells - drug effects; Myeloid Cells - immunology; myeloid‐derived suppressor cell; notch1; Notch1 protein; PD-1 protein; Protein-Serine-Threonine Kinases - physiology; PTEN Phosphohydrolase - physiology; PTEN protein; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Receptors, Transforming Growth Factor beta - physiology; regulatory T cell; Secretase; Signal transduction; Squamous cell carcinoma; Suppressor cells; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Thiazoles - pharmacology; Tissues; Tumor cells; Tumor Cells, Cultured; Tumor Escape - drug effects; Tumors; tumour‐associated macrophage
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.31115

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. What's new? Tumor survival depends on sneaking past the body's own immune defenses. Here, the authors probed how cancer cells exploit the Notch signaling pathway to evade immune destruction. Looking at HNSCC cells, they first showed that Notch1 signaling is activated in the tumor cells. Then, they showed that inhibiting the Notch signaling pathway decreased the tumor burden, as well as markedly reducing the production of immunosuppressive cells, such as tumor associated macrophages and immunosuppressive regulatory T cells. Thus, treatments targeting Notch1 could be useful against HNSCC.