Abstract
The innate immunoregulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells to stimulate antitumor T-cell immunity. Here, we show that STING signaling is recurrently suppressed in melanoma cells, where this event may enable immune escape after DNA damage. Mechanistically, STING signaling was suppressed most frequently by epigenetic silencing of either STING or the cyclic GMP-AMP synthase, which generates STING-activating cyclic dinucleotides after binding cytosolic DNA species. Loss of STING function rendered melanoma cells unable to produce type I IFN and other immune cytokines after exposure to cytosolic DNA species. Consequently, such cells were highly susceptible to infection with DNA viruses including HSV1, a variant of which is being developed presently as a therapeutic oncolytic virus [talimogene laherparepvec (T-VEC)]. Our findings provide insight into the basis for susceptibility to viral oncolysis by agents such as HSV1.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6747-6759 |
| Number of pages | 13 |
| Journal | Cancer Research |
| Volume | 76 |
| Issue number | 22 |
| DOIs | |
| State | Published - Nov 15 2016 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
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Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis. / Xia, Tianli; Konno, Hiroyasu; Barber, Glen N.
In: Cancer Research, Vol. 76, No. 22, 15.11.2016, p. 6747-6759.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis
AU - Xia, Tianli
AU - Konno, Hiroyasu
AU - Barber, Glen N
PY - 2016/11/15
Y1 - 2016/11/15
N2 - The innate immunoregulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells to stimulate antitumor T-cell immunity. Here, we show that STING signaling is recurrently suppressed in melanoma cells, where this event may enable immune escape after DNA damage. Mechanistically, STING signaling was suppressed most frequently by epigenetic silencing of either STING or the cyclic GMP-AMP synthase, which generates STING-activating cyclic dinucleotides after binding cytosolic DNA species. Loss of STING function rendered melanoma cells unable to produce type I IFN and other immune cytokines after exposure to cytosolic DNA species. Consequently, such cells were highly susceptible to infection with DNA viruses including HSV1, a variant of which is being developed presently as a therapeutic oncolytic virus [talimogene laherparepvec (T-VEC)]. Our findings provide insight into the basis for susceptibility to viral oncolysis by agents such as HSV1.
AB - The innate immunoregulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells to stimulate antitumor T-cell immunity. Here, we show that STING signaling is recurrently suppressed in melanoma cells, where this event may enable immune escape after DNA damage. Mechanistically, STING signaling was suppressed most frequently by epigenetic silencing of either STING or the cyclic GMP-AMP synthase, which generates STING-activating cyclic dinucleotides after binding cytosolic DNA species. Loss of STING function rendered melanoma cells unable to produce type I IFN and other immune cytokines after exposure to cytosolic DNA species. Consequently, such cells were highly susceptible to infection with DNA viruses including HSV1, a variant of which is being developed presently as a therapeutic oncolytic virus [talimogene laherparepvec (T-VEC)]. Our findings provide insight into the basis for susceptibility to viral oncolysis by agents such as HSV1.
UR - http://www.scopus.com/inward/record.url?scp=84995477297&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84995477297&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-16-1404
DO - 10.1158/0008-5472.CAN-16-1404
M3 - Article
C2 - 27680683
AN - SCOPUS:84995477297
VL - 76
SP - 6747
EP - 6759
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 22
ER -