Kinase Inhibitor Sorafenib Modulates Immunosuppressive Cell Populations in a Murine Liver Cancer Model

Overview

Journal Lab Invest

Specialty Pathology

Date 2011 Feb 16

PMID 21321535

Citations 63

Authors

Mengde Cao

Yiling Xu

Je-In Youn

Roniel Cabrera

Xiaokui Zhang

Dmitry Gabrilovich

David R Nelson

Chen Liu

Affiliations

Soon will be listed here.

Abstract

Accumulating evidence suggests that regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) are elevated in cancer patients and tumor-bearing hosts, and that depletion of Tregs and MDSC may enhance the anti-tumor immunity of the host. Sorafenib, a novel multi-kinase inhibitor, is approved for the treatment of several human cancers, including advanced hepatocellular carcinoma (HCC). Sorafenib is believed to inhibit tumor growth via anti-angiogenesis, cell cycle arrest, and inducing apoptosis. However, the impact of Sorafenib on immune cell populations in tumor-bearing hosts is unclear. In this report, we show that Tregs and MDSC are increased in the spleens and bone marrows of the BALB/c mice with liver hepatoma. The increase in Tregs and MDSC was positively correlated with tumor burden. Treatment of Sorafenib not only inhibited HCC cell growth in mice but also significantly decreased the suppressive immune cell populations: Tregs and MDSC. In conclusion, our study strongly suggests that Sorafenib can enhance anti-tumor immunity via modulating immunosuppressive cell populations in the murine liver cancer model.

Citing Articles

Advances in Immunotherapy in Hepatocellular Carcinoma.

Bloom M, Podder S, Dang H, Lin D Int J Mol Sci. 2025; 26(5).

PMID: 40076561 PMC: 11900920. DOI: 10.3390/ijms26051936.

Cellular polarity pilots breast cancer progression and immunosuppression.

Huang J, Luo S, Shen J, Lee M, Chen R, Ma S Oncogene. 2025; .

PMID: 40057606 DOI: 10.1038/s41388-025-03324-0.

Immune Microenvironment and the Effect of Vascular Endothelial Growth Factor Inhibition in Hepatocellular Carcinoma.

Oura K, Morishita A, Tadokoro T, Fujita K, Tani J, Kobara H Int J Mol Sci. 2025; 25(24.

PMID: 39769351 PMC: 11679663. DOI: 10.3390/ijms252413590.

High ratio of resident to exhausted CD4 + T cells predicts favorable prognosis and potentially better immunotherapeutic efficacy in hepatocellular carcinoma.

Zuo A, Lv J, Jia W, Ba Y, Liu S, Zhang Y BMC Cancer. 2024; 24(1):1152.

PMID: 39289669 PMC: 11409587. DOI: 10.1186/s12885-024-12916-0.

Sorafenib plus transcatheter arterial chemoembolization with or without camrelizumab for the treatment of intermediate and advanced hepatocellular carcinoma.

Sun B, Chen L, Lei Y, Zhang L, Sun T, Liu Y Br J Radiol. 2024; 97(1159):1320-1327.

PMID: 38711192 PMC: 11186562. DOI: 10.1093/bjr/tqae087.

References

HANSON H, Donermeyer D, Ikeda H, White J, Shankaran V, Old L . Eradication of established tumors by CD8+ T cell adoptive immunotherapy. Immunity. 2000; 13(2):265-76. DOI: 10.1016/s1074-7613(00)00026-1. View

Greten T, Manns M, Korangy F . Immunotherapy of HCC. Rev Recent Clin Trials. 2008; 3(1):31-9. DOI: 10.2174/157488708783330549. View

Gonzalez-Carmona M, Marten A, Hoffmann P, Schneider C, Sievers E, Schmidt-Wolf I . Patient-derived dendritic cells transduced with an a-fetoprotein-encoding adenovirus and co-cultured with autologous cytokine-induced lymphocytes induce a specific and strong immune response against hepatocellular carcinoma cells. Liver Int. 2006; 26(3):369-79. DOI: 10.1111/j.1478-3231.2005.01235.x. View

Llovet J, Bruix J . Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008; 48(4):1312-27. PMC: 2597642. DOI: 10.1002/hep.22506. View

Abelev G, Eraiser T . Cellular aspects of alpha-fetoprotein reexpression in tumors. Semin Cancer Biol. 1999; 9(2):95-107. DOI: 10.1006/scbi.1998.0084. View

Sato N, Michaelides M, Wallack M . Characterization of tumorigenicity, mortality, metastasis, and splenomegaly of two cultured murine colon lines. Cancer Res. 1981; 41(6):2267-72. View

Zhang H, Zhang L, Ren J, Fan L, Si X, Liu W . Induction of alpha-fetoprotein-specific CD4- and CD8-mediated T-cell response using RNA-transfected dendritic cells. Cell Immunol. 2006; 239(2):144-50. DOI: 10.1016/j.cellimm.2006.05.004. View

Wang X, Revskaya E, Bryan R, Strickler H, Burk R, Casadevall A . Treating cancer as an infectious disease--viral antigens as novel targets for treatment and potential prevention of tumors of viral etiology. PLoS One. 2007; 2(10):e1114. PMC: 2040508. DOI: 10.1371/journal.pone.0001114. View

Rosenberg S . Progress in human tumour immunology and immunotherapy. Nature. 2001; 411(6835):380-4. DOI: 10.1038/35077246. View

10.

Cao M, Cabrera R, Xu Y, Firpi R, Zhu H, Liu C . Hepatocellular carcinoma cell supernatants increase expansion and function of CD4(+)CD25(+) regulatory T cells. Lab Invest. 2007; 87(6):582-90. DOI: 10.1038/labinvest.3700540. View

11.

Zitvogel L, Mayordomo J, Tjandrawan T, DeLeo A, Clarke M, Lotze M . Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines. J Exp Med. 1996; 183(1):87-97. PMC: 2192415. DOI: 10.1084/jem.183.1.87. View

12.

Kobayashi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge T . FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res. 2007; 13(3):902-11. DOI: 10.1158/1078-0432.CCR-06-2363. View

13.

Alisa A, Ives A, Pathan A, Navarrete C, Williams R, Bertoletti A . Analysis of CD4+ T-Cell responses to a novel alpha-fetoprotein-derived epitope in hepatocellular carcinoma patients. Clin Cancer Res. 2005; 11(18):6686-94. DOI: 10.1158/1078-0432.CCR-05-0382. View

14.

Patek P, Collins J, Cohn M . Transformed cell lines susceptible or resistant to in vivo surveillance against tumorigenesis. Nature. 1978; 276(5687):510-1. DOI: 10.1038/276510a0. View

15.

Youn J, Nagaraj S, Collazo M, Gabrilovich D . Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol. 2008; 181(8):5791-802. PMC: 2575748. DOI: 10.4049/jimmunol.181.8.5791. View

16.

Cheng P, Corzo C, Luetteke N, Yu B, Nagaraj S, Bui M . Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med. 2008; 205(10):2235-49. PMC: 2556797. DOI: 10.1084/jem.20080132. View

17.

Nagaraj S, Gabrilovich D . Myeloid-derived suppressor cells. Adv Exp Med Biol. 2007; 601:213-23. DOI: 10.1007/978-0-387-72005-0_22. View

18.

Shibolet O, Alper R, Zlotogarov L, Thalenfeld B, Engelhardt D, Rabbani E . Suppression of hepatocellular carcinoma growth via oral immune regulation towards tumor-associated antigens is associated with increased NKT and CD8+ lymphocytes. Oncology. 2004; 66(4):323-30. DOI: 10.1159/000078334. View

19.

Stift A, Friedl J, Dubsky P, Bachleitner-Hofmann T, Schueller G, Zontsich T . Dendritic cell-based vaccination in solid cancer. J Clin Oncol. 2002; 21(1):135-42. DOI: 10.1200/JCO.2003.02.135. View

20.

Cabrera R, Ararat M, Cao M, Xu Y, Wasserfall C, Atkinson M . Hepatocellular carcinoma immunopathogenesis: clinical evidence for global T cell defects and an immunomodulatory role for soluble CD25 (sCD25). Dig Dis Sci. 2009; 55(2):484-95. PMC: 3161029. DOI: 10.1007/s10620-009-0955-5. View