Abstract
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.
Original language | English (US) |
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Pages (from-to) | 2137-2152 |
Number of pages | 16 |
Journal | Cancer research |
Volume | 76 |
Issue number | 8 |
DOIs | |
State | Published - Apr 15 2016 |
ASJC Scopus subject areas
- Oncology
- Cancer Research