1. Inhibition of SRC family kinases facilitates anti-CTLA4 immunotherapy in head and neck squamous cell carcinoma
- Author
-
Hao Wu, Lei Wu, Lin-Lin Bu, Guang-Tao Yu, Zhi-Jun Sun, Wei-Wei Deng, Jian-Feng Liu, Liang Mao, Lei Chen, Wen-Feng Zhang, and Lei-Lei Yang
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,medicine.medical_treatment ,Dasatinib ,Receptor, Transforming Growth Factor-beta Type I ,CD8-Positive T-Lymphocytes ,Mice ,0302 clinical medicine ,Tumor Microenvironment ,CTLA-4 Antigen ,Mice, Knockout ,biology ,Kinase ,Antibodies, Monoclonal ,src-Family Kinases ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Molecular Medicine ,Drug Therapy, Combination ,Immunotherapy ,medicine.drug ,STAT3 Transcription Factor ,Combination therapy ,Down-Regulation ,chemical and pharmacologic phenomena ,Protein Serine-Threonine Kinases ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Immune system ,medicine ,Animals ,PTEN ,Protein Kinase Inhibitors ,Molecular Biology ,Pharmacology ,Tumor microenvironment ,Squamous Cell Carcinoma of Head and Neck ,business.industry ,PTEN Phosphohydrolase ,Cell Biology ,medicine.disease ,Head and neck squamous-cell carcinoma ,Disease Models, Animal ,030104 developmental biology ,Cancer research ,biology.protein ,business ,Receptors, Transforming Growth Factor beta - Abstract
The immune system plays a critical role in the establishment, development, and progression of head and neck squamous cell carcinoma (HNSCC). As treatment with single-immune checkpoint agent results in a lower response rate in patients, it is important to investigate new strategies to maintain favorable anti-tumor immune response. Herein, the combination immunotherapeutic value of CTLA4 blockade and SFKs inhibition was assessed in transgenic HNSCC mouse model. Our present work showed that tumor growth was not entirely controlled when HNSCC model mice were administered anti-CTLA4 chemotherapeutic treatment. Moreover, it was observed that Src family kinases (SFKs) were hyper-activated and lack of anti-tumor immune responses following anti-CTLA4 chemotherapeutic treatment. We hypothesized that activation of SFKs is a mechanism of anti-CTLA4 immunotherapy resistance. We, therefore, carried out combined drug therapy using anti-CTLA4 mAbs and an SFKs' inhibitor, dasatinib. As expected, dasatinib and anti-CTLA4 synergistically inhibited tumor growth in Tgfbr1/Pten 2cKO mice. Furthermore, dasatinib and anti-CTLA4 combined to reduce the number of myeloid-derived suppressor cells and Tregs, increasing the CD8+ T cell-to-Tregs ratio. We also found that combining dasatinib with anti-CTLA4 therapy significantly attenuated the expression of p-STAT3Y705 and Ki67 in tumoral environment. These results suggest that combination therapy with SFKs inhibitors may be a useful therapeutic approach to increase the efficacy of anti-CTLA4 immunotherapy in HNSCC.
- Published
- 2018