Department of Cell Biology and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
Cancer Res. 2016 Nov 15;76(22):6747-6759. doi: 10.1158/0008-5472.CAN-16-1404. Epub 2016 Sep 28.
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.
先天免疫调节剂 STING 可刺激细胞溶质 DNA 存在时的细胞因子产生，而细胞溶质 DNA 可在 DNA 损伤后产生。抗原呈递细胞也需要外在的 STING 信号来刺激抗肿瘤 T 细胞免疫。在这里，我们表明，黑色素瘤细胞中 STING 信号经常受到抑制，这种事件可能在 DNA 损伤后导致免疫逃逸。从机制上讲，STING 信号最常被 STING 或环鸟苷酸-腺苷酸合酶的表观遗传沉默所抑制，后者在结合细胞溶质 DNA 后产生激活 STING 的环二核苷酸。STING 功能丧失使黑色素瘤细胞在暴露于细胞溶质 DNA 后无法产生 I 型 IFN 和其他免疫细胞因子。因此，这些细胞对包括单纯疱疹病毒 1（HSV1）在内的 DNA 病毒的感染高度敏感，其中 HSV1 的一种变体目前正在作为一种治疗性溶瘤病毒（talimogene laherparepvec[T-VEC]）进行开发。我们的研究结果为 HSV1 等药物对溶瘤作用的敏感性提供了依据。癌症研究；76(22)；6747-59。©2016AACR。
