| Popis: |
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. Here we will use a combination of in vitro systems, animal models, and samples from first in human clinical trials of the CD11b-agonist to identify the mechanism of action of this approach and identify combinations for further testing. CD11b agonism alters 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, contributing to suppressing myeloid cells infiltration. In contrast, CD11b agonism triggers mitochondrial dysfunction to stimulate STING-induced, STAT1-mediated interferon signaling, contributing to macrophages-augmented anti-tumor T cell immunity. Tissues from phase I clinical trials shows that CD11b agonist activates STING and STAT1 signaling in TAMs in human tumors, which is in consistent with preclinical data. Furthermore, combining CD11b agonism with cytotoxic therapies, STING agonist or TLRs agonists leads to robust anti-tumor activity in PDAC models. These studies pave the way for mechanism-based therapeutic combination strategies in cancer patients. Citation Format: Xiuting Liu, Graham Hogg, Chong Zuo, John Baer, Varintra Lander, Liang Kang, Nicholas Borcherding, Brett Knolhoff, Robin Osterhout, Anna Galkin, Jean Bruey, Laura Carter, Cedric Mpoy, Julie Schwarz, Haeseong Park, Vineet Gupta, David DeNardo. Context-dependent induction of interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5964. |
