Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells

作者：Tang Chih Hang Anthony; Zundell Joseph A; Ranatunga Sujeewa; Lin Cindy; Nefedova Yulia; Del Valle Juan R; Hu Chih Chi Andrew^*

来源：Cancer Research, 2016, 76(8): 2137-2152.

DOI：10.1158/0008-5472.CAN-15-1885

Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In Em-TCL1 mice with chronic lymphocytic leukemia, injection of the STING agonist 3'3'-cGAMP induced apoptosis and tumor regression. Similarly efficacious effects were elicited by 3'3'-cGAMP injection in syngeneic or immunodeficient mice grafted with multiple myeloma. Thus, in addition to their established ability to boost antitumoral immune responses, STING agonists can also directly eradicate malignant B cells.

• 出版日期2016-4-15