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

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, interferon 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 Eμ-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 anti-tumoral immune responses, STING agonists can also directly eradicate malignant B cells.

Cutting Edge: Activation of STING in T Cells Induces Type I IFN Responses and Cell Death

“…T cells are known to express various PRR that provide co-stimulatory signals (19, 20), but TCR-independent cytosolic DNA-sensing could be uniquely useful to allow surveillance of infection or DNA damage in T cells and enable self-destruction, preventing infected or damaged and potentially cancerous T cells from proliferating and causing disease. These findings complement a recent report by Tang et al demonstrating CDN-induced apoptosis in B cells and B cell lymphomas (21). But while they concluded this response was B cell-specific because no effect on T cells was observed with in vitro cGAMP treatment, our DMXAA and R'ScGAMP experiments conclusively demonstrate T cells are responsive to STING activation.…”

Decreased Expression of TMEM173 Predicts Poor Prognosis in Patients with Hepatocellular Carcinoma

“…TMEM173 might also play a role in the anti-tumor effect through influencing checkpoint inhibitors such as CTLA4 and PD1[22]. Meanwhile, activation of TMEM173 could directly induce cell apoptosis and autophagy in malignant cells[23], which might inhibit tumor growth.…”

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

“…Among an array innate immune signaling molecules examined for an essential role in tumor growth and immunogenicity, STING and cGAS appear to be uniquely indispensable for natural or spontaneous anti-tumor immunity [42 •• ,43 •• ], as well as the immunogenic effects of irradiation [44 •• ], CD47 blockade [45], and immune checkpoint therapy [46]. Accordingly, cGAMP is a potent anti-tumor agent against many solid and suspension tumor types [47–50]. In addition to modulation of tumor immunogenicity, STING agonists have been demonstrated to directly affect tumor cells by promoting induction of apoptosis in breast tumor cells [51], transformed B cells [50] and transformed T cells [52].…”

“…Accordingly, cGAMP is a potent anti-tumor agent against many solid and suspension tumor types [47–50]. In addition to modulation of tumor immunogenicity, STING agonists have been demonstrated to directly affect tumor cells by promoting induction of apoptosis in breast tumor cells [51], transformed B cells [50] and transformed T cells [52]. Notably, the cell-intrinsic response of tumor cells to STING agonists is variable, depending on cancer cell type and whether the signaling pathway is intact.…”