Inhibition of SRC family kinases reduces myeloid‐derived suppressor cells in head and neck cancer

• Published in: International journal of cancer Vol. 140; no. 5; pp. 1173 - 1185
• Main Authors: Mao, Liang, Deng, Wei‐Wei, Yu, Guang‐Tao, Bu, Lin‐Lin, Liu, Jian‐Feng, Ma, Si‐Rui, Wu, Lei, Kulkarni, Ashok B., Zhang, Wen‐Feng, Sun, Zhi‐Jun
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2017
• Subjects: Animals; Cancer; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - pathology; Dasatinib - pharmacology; Dasatinib - therapeutic use; Enzyme Induction - drug effects; Epithelial Cells - enzymology; Gene Expression Regulation, Neoplastic - drug effects; Head & neck cancer; head and neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - enzymology; Head and Neck Neoplasms - immunology; Head and Neck Neoplasms - pathology; Humans; Kinases; LYN kinase; Medical research; Mice; Mice, Knockout; Molecular Targeted Therapy; Myeloid-Derived Suppressor Cells - pathology; myeloid‐derived suppressor cell; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - physiology; Phosphorylation; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Processing, Post-Translational - drug effects; Protein-Serine-Threonine Kinases - deficiency; PTEN Phosphohydrolase - deficiency; Receptors, Transforming Growth Factor beta - deficiency; SRC family kinase; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - biosynthesis; src-Family Kinases - genetics; src-Family Kinases - metabolism; src-Family Kinases - physiology; Stromal Cells - enzymology; Tumor Escape; Up-Regulation; Xenograft Model Antitumor Assays; SRC family kinase; head and neck cancer; myeloid-derived suppressor cell; LYN kinase
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30493

SRC family kinases (SFKs), a group of nonreceptor tyrosine kinases, modulate multiple cellular functions, such as cell proliferation, differentiation and metabolism. SFKs display aberrant activity in progressive stages of human cancers. However, the precise role of SFKs in the head and neck squamous cell carcinoma (HNSCC) signaling network is far from clear. In this study, we found that the inhibition of SFKs activity by dasatinib effectively reduced the tumor size and population of MDSCs in the HNSCC mouse model. Molecular analysis indicates that phosphorylation of LYN, rather than SRC, was inhibited by dasatinib treatment. Next, we analyzed LYN expression by immunostaining and found that it was overexpressed in the human HNSCC specimens. Moreover, LYN expression in stromal cells positively correlated with myeloid‐derived suppressor cells (MDSCs) makers CD11b and CD33 in human HNSCC. The dual positive expression of LYN in epithelial and stromal cells (EPI+ SRT+) was associated with unfavorable overall survival of HNSCC patients. These findings indicate that SFKs may be a potential target for an effective immunotherapy of HNSCC by decreasing MDSCs and moreover, LYN will have an impact on such therapeutic strategy. What's new? The complex interaction between cancer cells and their surrounding microenvironment play important roles in tumor progression. A common target for both cancer and stromal cells in head and neck cancer is not well defined. Here, the authors revealed that SFKs inhibition can simultaneously reduce tumor size and MDSCs in vivo. LYN may have an impact in this treatment. Elevated LYN expression in human specimens was associated with MDSCs markers and poor overall survival. Head and neck squamous cell carcinoma (HNSCC) is a complex disease, involving mutations in multiple oncogenic pathways and cellular interactions in the tumor microenvironment. Existing HNSCC therapies are aimed primarily at disrupting pathways in tumor cells. The present study shows, however, that targeting factors that influence the tumor microenvironment, specifically SRC family kinases (SFKs), can potentially halt HNSCC progression. In mice, the SFK inhibitor dasatinib effectively reduced HNSCC growth and caused declines in populations of myeloid‐derived suppressor cells. The drug specifically blocked phosphorylation of LYN tyrosine kinase, overexpression of which in human specimens was associated with poor overall survival.