Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases

Abstract

AbstractBackgroundThe interferon response can influence the primary and metastatic activity of breast cancers and can interact with checkpoint immunotherapy to modulate its effects. UsingN-ethyl-N-nitrosourea mutagenesis, we found a mouse with an activating mutation in oligoadenylate synthetase 2 (Oas2), a sensor of viral double stranded RNA, that resulted in an interferon response and prevented lactation in otherwise healthy mice.MethodsTo determine if sole activation ofOas2could alter the course of mammary cancer, we combined theOas2mutation with theMMTV-PyMToncogene model of breast cancer and examined disease progression and the effects of checkpoint immunotherapy using Kaplan–Meier survival analysis with immunohistochemistry and flow cytometry.ResultsOas2mutation prevented pregnancy from increasing metastases to lung. Checkpoint immunotherapy with antibodies against programmed death-ligand 1 was more effective when theOas2mutation was present.ConclusionsThese data establish OAS2 as a therapeutic target for agents designed to reduce metastases and increase the effectiveness of checkpoint immunotherapy.