|Dai Liu, Xiaoqiang Qi, Yariswamy Manjunath, Eric T. Kimchi, Lixin Ma, Jussuf T. Kaifi, Kevin F. Staveley-O’Carroll*and Guangfu Li*|
|Corresponding Author: Kevin F. Staveley-O’Carroll, M.D., Ph.D., Professor, Chair of Surgery, Director of Ellis Fischel Cancer Center, One Hospital Drive, Mc501, University of Missouri-Columbia, Columbia, MO 65212, Tel: 573-882-4158; Fax: 573-884-4585; E-mail: firstname.lastname@example.org Guangfu & Li, Ph.D., DVM., Assistant Professor, Department of Surgery, Molecular Microbiology and Immunolgy, Ellis Fischel Cancer Center, University of Missouri-Columbia, One Hospital Dr., Medical Sciences Building, M272, Columbia, MO 65212, Tel: 573-882-7124 (Office), Fax: 573-884-4585, E-mail: email@example.com|
|Received: July 3, 2017; Accepted: July 19, 2017;|
|Citation: Liu D, Qi X, Manjunath Y, Kimchi E T, Ma L, et al. (2017) Sunitinib and Sorafenib Modulating Antitumor Immunity in Hepatocellular Cancer. J Immunol Res Ther, 2(2): 115-123.|
|Copyrights: ©2017 Liu D, Qi X, Manjunath Y, Kimchi E T, Ma L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.|
Sorafenib and sunitinib are multiple tyrosine kinase inhibitors. Both of them have been approved by the US FDA in the treatment of patients with malignancies. In order to develop an effective and clinically useful chemoimmunotherapy modality against hepatocellular cancer (HCC), we investigate their tumoricidal and immune modulatory effect in the setting of HCC. In vitro experiments suggested that sunitinib and sorafenib both induced HCC cell apoptosis at an equivalent level, but stronger suppressive function to cell proliferation was detected in sorafenib. Correspondingly, treatment of tumor-bearing mice with sorafenib led to the suppression of tumor growth to a larger extent than sunitinib. Flow cytometry showed that treatment with sunitinib, not sorafenib, significantly reduced the frequency of regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) in tumor-bearing mice; and allowed splenic lymphocytes to produce equivalent levels of IFN-γ and TNF-α in response to vaccination as that in wild type mice. This activation was not detected in control and sorafenib-treated tumor mice. In addition, treatment of tumor-bearing mice with sunitinib followed by adoptive transfer of tumor antigen-specific CD8+ T cells and immunization resulted in the additional suppression to tumor growth compared to sunitinib monotherapy. These results imply treatment with sunitinib, not sorafenib, is able to prevent tumor-induced immunotolerance and activate antitumorimmunity. Our data suggest that sunitinib may be a preferable chemotherapeutic agent to use in combination with immunotherapy for the treatment of HCC.
Keywords: Hepatocellular cancer (HCC), Sunitinib, Sorafenib, Chemoimmunotherapy, Regulatory T cells (Tregs), Myeloid-derived suppressive cells (MDSCs)
Abbreviations: CCl4 : Carbon tetrachloride; CTLA-4: Cytotoxic T-lymphocyte-associated Protein 4; HCC: Hepatocellular Cancer; IP: Intraperitoneal; ISPL: Intra-splenic; MDSC: Myeloid-derived Suppressor Cell; MRI: Magnetic Resonance Imaging; PD-1: Programmed Cell Death Protein 1; PD-L1: Programmed Death-1 Ligand; RCC: Renal Cell Cancer ; SOR: Sorafenib; SU: Sunitinib; TAg: SV40 T antigen; TCR: T Cell Receptor.