Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels

To investigate whether IL-6 signaling affects the susceptibility of castration resistant prostate cancer (CRPC) cells to cytotoxic action of natural killer (NK) cells, CRPC cell lines (having different IL-6 level) were developed by lentiviral transduction. While observing no secreted IL-6 level in parental C4-2 and CWR22Rv1 cells, we found the IL-6 expression/secretion in these cells was induced after the transduction process and the IL-6 level difference in C4-2siIL-6/sc and CWR22siIL-6/sc cell CRPC cell sets could be detected. We then found that IL-6 knocked down cells were more susceptible to NK cell cytotoxicity than control cells due to lowered programmed death receptor ligand 1 (PD-L1) and increased NK group 2D (NKG2D) ligand levels. In animal studies, to concur with the in vitro results, we found that IL-6 expressing cells-derived tumors were more resistant to NK cell action than the tumors of IL-6 knocked down cells. Further, we discovered that JAK-Stat3 is the most critical IL-6 downstream signaling that modulates PD-L1/NKG2D ligand levels in CRPC cells. Furthermore, inhibition of the JAK or Stat3 signaling effectively increased the susceptibility of C4-2sc and CWRsc cells to NK cell cytotoxicity. We observed the most effective cytotoxicity when the PD-L1 Ab and JAK inhibitor (or Stat 3 inhibitor) were used together. These results suggest that the strategy of targeting IL-6 signaling (or its downstream signaling) may enhance the NK cell-mediated immune action to CRPC tumors, thus yielding clinical implications in developing future immunotherapeutics of exploiting this strategy to treat CRPC patients.

Molecular oncology. 2017 Sep 02 [Epub ahead of print]

LiJun Xu, XiaoDong Chen, MingJing Shen, Dong-Rong Yang, Laifu Fang, Guobin Weng, Ying Tsai, Peter C Keng, Yuhchyau Chen, Soo Ok Lee

Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA., Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, P.R. China., Department of Pathology, Ningbo Yin Zhou Hospital, Ningbo, Zhejiang, 315100, P.R. China., Department of Urology, Ningbo Urology and Nephrology Hospital, Ningbo, Zhejiang, 315100, P.R. China.