Abstract 4063: The oncogenic cell cycle-related kinase promotes tumor immune escape via modulation of myeloid-derived suppressor cells in hepatocellular carcinoma
Authors: Zhou Jingying , Cheng Alfred Sze Lok , Chen Zhiwei 
Published: August 2015

Hepatocellular carcinoma (HCC) is a sexually dimorphic cancer significantly associated with elevated levels of male sex hormone androgen and pro-inflammatory cytokine interleukin-6 (IL-6) (ref 1). Our previous genome-wide location and functional analysis has pinpointed cell cycle-related kinase (CCRK) as a critical mediator of androgen receptor (AR) oncogenic activity in HCC through a self-reinforcing circuitry involving β-catenin and the Polycomb repressor enhancer of zeste 2 (EZH2) (ref 2-4). As these key circuit players have also been shown to trigger inflammatory response and aggressiveness of HCC cells (ref 5,6), we aimed to investigate whether CCRK modulates tumor microenvironment during hepatocarcinogenesis. Expression profiling of 16 pro-inflammatory cytokines and chemokines revealed that ectopic expression of wild-type but not kinase-defective CCRK significantly induced the production of IL-6, IL-1β, tumor necrosis factor-α and cyclooxygenase 2 in immortal hepatic and HCC cells. Rescue experiments showed that CCRK-induced IL-6 production was dependent on EZH2 up-regulation and subsequent nuclear factor-κB activation. Based on the causal link between IL-6 and myeloid-derived suppressor cells (MDSCs), we next examined the relationship between CCRK and MDSCs in vitro and in vivo. By co-culturing CCRK-expressed or silenced hepatic and HCC cell lines with peripheral blood mononuclear cells (PBMCs) isolated from healthy donors, we found that CCRK stimulated the expansion of Lin-CD33+CD11b+HLA-DR-MDSCs from PBMCs by flow cytometry analysis. The induced MDSCs also showed higher suppressive activity against CD3+ T cell proliferation. In a high-fat diet-fed mouse model exposed to low-dose carcinogen diethylnitrosamine, administration of lentivirus expressing short-hairpin (sh)RNA against Ccrk significantly reduced &gt;70% obesity-promoted tumor multiplicity and size compared to mice treated with control shRNA (p&lt;0.01). Notably, Ccrk down-regulation also significantly reduced the population of circulating CD11b+Gr-1intMDSCs in the mice (p&lt;0.05). In summary, our findings demonstrate that the oncogenic CCRK in hepatic cells can promote MDSC expansion and suppressive functions possibly via IL-6 production. Such tumor-stromal cell interaction provides survival advantage of cancer cells via immune escape. In conclusion, CCRK not only functions as a signaling hub but also an immunoregulator, thus representing a new cancer immunotherapy target.

References:

1. Tian Y et al., Semin Cancer Biol 2013

2. Feng H et al., J Clin Invest 2011

3. Yu Z et al., Gut 2014

4. Feng H et al., J Hepatol in press

5. Anson M et al., J Clin Invest 2012

6. Zheng F et al., Gut 2012

Citation Format: Jingying Zhou, Alfred Sze Lok Cheng, Zhiwei Chen. The oncogenic cell cycle-related kinase promotes tumor immune escape via modulation of myeloid-derived suppressor cells in hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4063. doi:10.1158/1538-7445.AM2015-4063