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. Cancer Res; 76(22); 6747-59. ©2016 AACR.
Highlights
Skin cancer is the most common form of cancer in the United States, and melanoma, affecting about 1.2 million people in the United States, accounts for the vast majority of skin cancer–related deaths
To evaluate whether this key pathway is defective in other types of cancer, we further examined stimulator of IFN genes (STING) expression by immunoblot in a panel of human malignant melanomas
This study indicated that all 11 melanoma cells responded poorly to STING-dependent, dsDNA-triggered type I IFN production
Summary
Skin cancer is the most common form of cancer in the United States, and melanoma, affecting about 1.2 million people in the United States, accounts for the vast majority of skin cancer–related deaths. Basal cell and squamous cell skin cancer responds well to treatment, especially if the cancer is detected and cared for early, cutaneous melanomas are usually difficult to treat especially when diagnosed in advanced stages. Oncolytic virotherapy is a novel anticancer treatment that generally uses genetically engineered viruses to infect and lyse cancer tissue. Amgen talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1 (HSV-1)–based OV that has been engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF), which may facilitate tumor clearance. It has Department of Cell Biology and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
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