Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients

Abstract

Chronic activation of inflammatory pathways and suppressed interferon signaling are hallmarks of myeloid cells in immunosuppressive tumors that drive poor responsiveness to conventional and immune therapies. Previous studies have identified agonistic activation of the CD11b integrin as a potential strategy to enhance anti-tumor immunity. However, the mechanisms by which CD11b-agonism reprogram tumor immunity are poorly understood, and this may impair patient selection and identification of effective treatment combinations. Herein we used a combination of in vitro systems, animal models, and samples from first in human clinical trials of the CD11b-agonist GB1275 to identify the mechanism of action of this approach and identify combinations for further testing. We found that CD11b agonism altered tumor-associated macrophage (TAM) phenotypes by simultaneously repressing NFκB/IL1-signaling and activating interferon (IFN) gene expression. Repression of NFκB/IL-1 signaling was due to rapid degradation of p65 protein by the proteosome and was not context dependent. In contrast, CD11b agonism triggered mitochondrial dysfunction to stimulate STING-induced, STAT1-mediated interferon signaling. The magnitude of CD11b agonist induction of STING/IFN signaling was dependent on the tumor microenvironment and was significantly amplified by cytotoxic therapies. Using tissues from phase I clinical trials, we demonstrated that GB1275 treatment activated STING and STAT1 signaling in TAMs in human tumors. Together, these mechanisms allowed macrophages to augment anti-tumor T cell immunity. These studies identified potential mechanism-based therapeutic strategies for CD11b agonist use and identified potential patient populations more likely to benefit from them.

STING signaling in inflammaging: a new target against musculoskeletal diseases

“…Formation of the Atg5-Atg12-Atg16L complex, located on the outside of the phagophore membrane, recruits light chain 3 (LC3) for processing and maturation in the next stage ( 3 ). Microtubule-associated protein LC3 is processed into a lipidated form (LC3 lipidation) and inserted into the extending phagophore membrane, leading to the maturation of the autophagosome ( 4 ). The autophagosome captures the material to be degraded, which can be either random or selective ( 5 ).…”

“…Activation of STING plays a crucial role in defending against pathogen invasion and promoting anti-tumor immunity. For instance, STING activation can induce cellular senescence, promote dendritic cell maturation, and other mechanisms to exhibit anti-tumor effects (3,4). Studies using STING agonists alone or in combination with other drugs have shown promising results, such as the use of STING agonist DMXAA in combination with chemotherapy drug SN38, which demonstrated strong antitumor effects in melanoma and colon cancer (5)(6)(7).…”