153P - Tocilizumab can enhance the anti-tumor effect of IFN-α in renal cell carcinoma

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Renal Cell Cancer
Basic Science
Presenter Toshiki Oguro
Authors T. Oguro1, K. Ishibashi2, T. Sugino3, S. Kumagai2, N. Takahashi2, N. Haga2, T. Yanagida2, K. Aikawa2, O. Yamaguchi4, Y. Kojima2
  • 1Urology Dept., Fukushima Medical University, 9601295 - Fukushima/JP
  • 2Urology, Fukushima Medical University, 9601295 - Fukushima/JP
  • 3Pathology, Fukushima Medical University, 9601295 - Fukushima/JP
  • 4Bioenginnering, Nihon Uneversity, 9638642 - Koriyama/JP

Abstract

Background

Interleukin 6 (IL-6), one of the proinflammatory cytokines, contributes to the onset and maintenance of various types of cancer. IL-6 signaling induces up-regulation of SOCS3, which leads to interferon (IFN) –α resistance in renal cell carcinoma (RCC) cells. To propose a new treatment for mRCC, we investigated the effect of combination therapy with IFN-α and humanized antihuman IL-6R antibody, tocilizumab.

Material and methods

Real time PCR (RT-PCR) was used to analyze gene expression of IL-6 and SOCS3 after IFN stimulation and ELISA were used for IL-6 secretion in RCC cell lines. These expression levels were compared among the RCC cell lines, i.e., ACHN, Caki-1, TUHR3TKB, TUHR4TKB and 786-O. Phosphorylation of STAT-1, STAT-3 and ERK were investigated by Western blotting (WB) analysis. We investigated alteration of IL-6 signaling by tocilizumab, and analyzed its impacts on the susceptibility to IFN-α in RCC cells by MTT assay. The effects of tocilizumab on in vivo growth on 786-O xenografts were determined by SOCS3 expression, morphological observation and tumor volume.

Results

Among the RCC cell lines, the expression levels of IL-6, SOCS3 in RT-PCR and the production level of IL-6 were highest in 786-O. These results revealed a correlation between the expression levels IL-6 and SOCS3 (P = 0.0001, r = 0.99974). Although the 786-O cells had IFN-α resistance, MTT assay showed that the tocilizumab induced a growth inhibitory effect of IFN-α. WB analysis showed that phosphorylation level of STAT-1 was increased and the levels of STAT-3 and ERK were decreased with the simultaneous use of tocilizumab in 786-O cells. An in vivo study demonstrated that tocilizumab promoted IFN-α-induced cell death and growth suppression in 786-O cell xenograft in nude mice.

Conclusions

IL-6 could be a key component in the resistance to IFN-α treatment of renal cell carcinoma. Antihuman IL-6R antibody can be an effective strategy to enhance the anti-tumor effect of IFN-α, and probably, the effect of angiogenic inhibitors, in human RCC cells.

Disclosure

All authors have declared no conflicts of interest.