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.

Abstract

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 levels) 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-knockdown 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 cell-derived tumors were more resistant to NK cell action than the tumors of IL-6-knockdown 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 patients with CRPC.

• Authors: LiJun Xu, XiaoDong Chen, MingJing Shen, Dong-Rong Yang, Laifu Fang, Guobin Weng, Ying Tsai, Peter C Keng, Yuhchyau Chen, Soo Ok Lee
• Journal: Molecular oncology (Mol Oncol) Vol. 12 Issue 3 Pg. 269-286 (03 2018) ISSN: 1878-0261 [Electronic] United States
• PMID: 28865178 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• GPI-Linked Proteins
• Intercellular Signaling Peptides and Proteins
• Interleukin-6
• STAT3 Transcription Factor
• ULBP2 protein, human
• Janus Kinases

Topics

• Animals
• B7-H1 Antigen (genetics, metabolism)
• Cell Line, Tumor
• Cytotoxicity, Immunologic
• GPI-Linked Proteins (genetics, metabolism)
• Heterografts
• Humans
• Immunotherapy
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Interleukin-6 (antagonists & inhibitors, genetics, metabolism)
• Janus Kinases (antagonists & inhibitors, genetics, metabolism)
• Killer Cells, Natural (immunology)
• Male
• Mice
• Mice, Nude
• Primary Cell Culture
• Prostatic Neoplasms, Castration-Resistant (immunology, therapy)
• STAT3 Transcription Factor (antagonists & inhibitors)