Agonist-mediated activation of STING induces apoptosis in malignant B cells

Chih Hang Anthony Tang, Joseph A. Zundell, Sujeewa Ranatunga, Cindy Lin, Yulia Nefedova, Juan R. Del Valle, Chih Chi Andrew Hu

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

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 languageEnglish (US)
Pages (from-to)2137-2152
Number of pages16
JournalCancer research
Volume76
Issue number8
DOIs
StatePublished - Apr 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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