title: Combined blockade of Tim-3 and MEK inhibitor enhances the efficacy against melanoma.
abstract: Insights into the role of the mitogen-activated protein kinase (MAPK) pathway and immune checkpoints have led combined targeted therapy and immunotherapy to be a promising regimen. Trametinib, as a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, has demonstrated effectiveness in patients with advanced melanoma. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3), an immune checkpoint molecule, participates in multiple negative regulation of antitumor immunity. We for the first time to our knowledge reported the combination of trametinib and anti-Tim-3 monoclonal antibody (mAb) in treating B16-F10 melanoma mice. We discovered that trametinib remarkably promoted apoptosis and inhibited cell proliferation while inhibition of MEK improved the expression of Tim-3 and caused the decrease of CD8+T cells; to the contrary, anti-Tim-3 mAb enhanced antitumor immunity by stimulating CD8+T cells, thus the combined therapy produced potent antitumor effect cooperatively. Taken together, our study provides compelling evidence for combining trametinib and anti-Tim-3 mAb as a potential valuable regimen in treating melanoma.
authors.affiliation: Dept. of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: liuyang12378@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Dept. of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: caipengchengwh@aliyun.com.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Cai
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: wnll123@163.com.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Dept. of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: 344501842@qq.com.
authors.forename: Qianwen
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Dept. of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: Chfh100@126.com.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Chen
authors.affiliation: Dept. of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: liangshi7@126.com.
authors.forename: Liang
authors.initials: L
authors.lastname: Shi
authors.affiliation: Dept. of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: joyce9029@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Dept. of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: katelinwang@126.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Dept. of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: lihuahu@hust.edu.cn.
authors.forename: Lihua
authors.initials: L
authors.lastname: Hu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000037:antagonists & inhibitors*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D020930:MAP Kinase Kinase Kinases
keywords: Cancer immunotherapy; MAPK pathway; Targeted therapy; Tim-3; Trametinib