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

Autor: Yuhchyau Chen, Laifu Fang, Ying Tsai, Dong-Rong Yang, Xiaodong Chen, Soo Ok Lee, Mingjing Shen, Lijun Xu, Guobin Weng, Peter C. Keng
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Cytotoxicity
Immunologic
Male
Cancer Research
Cell
B7-H1 Antigen
NKG2D
Mice
0302 clinical medicine
Cytotoxic T cell
Receptor
Cytotoxicity
STAT3
Research Articles
General Medicine
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
3. Good health
Cell biology
Killer Cells
Natural
Prostatic Neoplasms
Castration-Resistant
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Molecular Medicine
Heterografts
Intercellular Signaling Peptides and Proteins
Immunotherapy
Research Article
castration‐resistant prostate cancer
STAT3 Transcription Factor
NK cell cytotoxicity
programmed death receptor ligand 1
Primary Cell Culture
Mice
Nude
Biology
GPI-Linked Proteins
lcsh:RC254-282
03 medical and health sciences
Immune system
Cell Line
Tumor
Genetics
medicine
Animals
Humans
Janus Kinases
Stat3
Interleukin-6
IL‐6
JAK
030104 developmental biology
Cell culture
biology.protein
Cancer research
Zdroj: Molecular Oncology
Molecular Oncology, Vol 12, Iss 3, Pp 269-286 (2018)
ISSN: 1878-0261
1574-7891
Popis: 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.
Databáze: OpenAIRE
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