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2018 ; 12
(3
): 269-286
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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
#MMPMID28865178
Xu L
; Chen X
; Shen M
; Yang DR
; Fang L
; Weng G
; Tsai Y
; Keng PC
; Chen Y
; Lee SO
Mol Oncol
2018[Mar]; 12
(3
): 269-286
PMID28865178
show ga
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.
|*Cytotoxicity, Immunologic
[MESH]
|Animals
[MESH]
|B7-H1 Antigen/genetics/*metabolism
[MESH]
|Cell Line, Tumor
[MESH]
|GPI-Linked Proteins/genetics/metabolism
[MESH]
|Heterografts
[MESH]
|Humans
[MESH]
|Immunotherapy
[MESH]
|Intercellular Signaling Peptides and Proteins/genetics/*metabolism
[MESH]