title: Axitinib augments antitumor activity in renal cell carcinoma via STAT3-dependent reversal of myeloid-derived suppressor cell accumulation.
abstract: Axitinib, a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), is used as an anti-angiogenic agent for the treatment of metastatic renal cell carcinoma (RCC). However, the effect of axitinib on antitumor immunity has remained largely unexplored. In this study, we show that while axitinib (25mg/kg) significantly suppresses tumor growth and metastasis, thus prolonging life span in murine RCC xenografts, the treatment leads to a major decrease in the number of myeloid-derived suppressor cells (MDSCs) in the spleens and tumor beds of animals, which in turn promotes antitumor responses of CD8+ T-cells in vivo. Moreover, as one of the main transcription factors that regulate MDSC function, Signal transducer and activator of transcription 3 (STAT3) was also significantly inhibited in the Renca tumor-associated MDSC and tumor tissues. These results suggest that axitinib has the potential to modulate antitumor immunity by downregulating STAT3 expression and reversing MDSC-mediated tumor-induced immunosuppression. The study reveals the unique antitumor mechanism of axitinib and provided useful information for its clinical application.
authors: Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China.
authors: Huaqin
authors: H
authors: Yuan
authors: Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China.
authors: Peifen
authors: P
authors: Cai
authors: Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China.
authors: Qian
authors: Q
authors: Li
authors: Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China.
authors: Weicheng
authors: W
authors: Wang
authors: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22, Hankou Road, Nanjing 210093, China. Electronic address: yangsun@nju.edu.cn.
authors: Yang
authors: Y
authors: Sun
authors: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22, Hankou Road, Nanjing 210093, China. Electronic address: molpharm@163.com.
authors: Qiang
authors: Q
authors: Xu
authors: Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China. Electronic address: guluer@163.com.
authors: Yanhong
authors: Y
authors: Gu
mesh_terms: D000818:Animals; D000077784:Axitinib; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D007093:Imidazoles; D007191:Indazoles; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000077784:Axitinib
keywords: Antitumor immunity; Axitinib; Myeloid-derived suppressor cells; Signal transducer and activator of transcription 3; Vascular endothelial growth factor receptor