Non-canonical STAT1 activation drives APC activation and potentiates tumor clearance.

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B949
Abstract ID: 6254

Presenting Author:
sunnie M Yoh , sr. Staff Scientist at Scripps Res.

Abstract:

The crucial role played by the innate immune system in both creating a proinflammatory tumor environment and priming T cells for generating tumor-specific responses highlights a potentially significant clinical strategy for the development of next-generation immunotherapies. Towards this end, we conducted a high-throughput screen to identify small molecule innate immune agonists capable of substantially activating antigen-presenting cells (APCs) and boosting anticancer immune responses. Through hit validation and in vivo characterization of compounds, we identified a series of cardiac glycosides (CGs) as potent inducers of dendritic cell activation in an ex vivo setting. Interestingly, we find that CGs, which are known to agonize Na+/K+ ATPase (NKA) pump activity on the plasma membrane, concomitantly induces Src-dependent p38 MAP kinase signaling and non-canonical STAT1 activation. Critically, we find that co-administration of Bufalin significantly enhanced the therapeutic efficacy of an oncolytic virus in a mouse melanoma model. Analysis of tumor tissues and tumor-draining lymph nodes revealed that the combinatorial treatment of the virus and CG led to a broad remodeling of the myeloid immune compartment, creating a proinflammatory state and enhancing T cell infiltration and priming. Our results suggest that harnessing the immunopotentiation properties of CGs can significantly improve the clinical efficacy of malignant tumor therapy.