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The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand
B7-H6 in tumor cells
#MMPMID27622013
Textor S
; Bossler F
; Henrich KO
; Gartlgruber M
; Pollmann J
; Fiegler N
; Arnold A
; Westermann F
; Waldburger N
; Breuhahn K
; Golfier S
; Witzens-Harig M
; Cerwenka A
Oncoimmunology
2016[Jul]; 5
(7
): e1116674
PMID27622013
show ga
Natural Killer (NK) cells are innate effector cells that are able to recognize
and eliminate tumor cells through engagement of their surface receptors. NKp30 is
a potent activating NK cell receptor that elicits efficient NK cell-mediated
target cell killing. Recently, B7-H6 was identified as tumor cell surface
expressed ligand for NKp30. Enhanced B7-H6 mRNA levels are frequently detected in
tumor compared to healthy tissues. To gain insight in the regulation of
expression of B7-H6 in tumors, we investigated transcriptional mechanisms driving
B7-H6 expression by promoter analyses. Using luciferase reporter assays and
chromatin immunoprecipitation we mapped a functional binding site for Myc, a
proto-oncogene overexpressed in certain tumors, in the B7-H6 promoter.
Pharmacological inhibition or siRNA/shRNA-mediated knock-down of c-Myc or N-Myc
significantly decreased B7-H6 expression on a variety of tumor cells including
melanoma, pancreatic carcinoma and neuroblastoma cell lines. In tumor cell lines
from different origin and primary tumor tissues of hepatocellular carcinoma
(HCC), lymphoma and neuroblastoma, mRNA levels of c-Myc positively correlated
with B7-H6 expression. Most importantly, upon inhibition or knock-down of c-Myc
in tumor cells impaired NKp30-mediated degranulation of NK cells was observed.
Thus, our data imply that Myc driven tumors could be targets for cancer
immunotherapy exploiting the NKp30/B7-H6 axis.
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