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

Wing-Hong Jonathan Ho; Andrew M K Law; Etienne Masle-Farquhar; Lesley E Castillo; Amanda Mawson; Moira K O'Bryan; Christopher C Goodnow; David Gallego-Ortega; Samantha R Oakes; Christopher J Ormandy

doi:10.1186/s13058-022-01525-z

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

Breast Cancer Res. 2022 May 3;24(1):31. doi: 10.1186/s13058-022-01525-z.

Authors

Wing-Hong Jonathan Ho^{1

2}, Andrew M K Law^{1

2}, Etienne Masle-Farquhar^{1

2}, Lesley E Castillo^{1

2}, Amanda Mawson^{1

2}, Moira K O'Bryan³, Christopher C Goodnow^{1

4}, David Gallego-Ortega^{1

2

5}, Samantha R Oakes^#^{1

2

6}, Christopher J Ormandy^#^{7

8}

Affiliations

¹ Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst Sydney, NSW, 2010, Australia.
² St. Vincent's Clinical School, St. Vincent's Hospital, UNSW Sydney, Kensington, NSW, Australia.
³ The School of BioSciences and Bio21 Institute, Faculty of Science, The University of Melbourne, Parkville, Melbourne, VIC, 3010, Australia.
⁴ Cellular Genomics Futures Institute, UNSW Sydney, Kensington, NSW, Australia.
⁵ School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, 81 Broadway, Ultimo Sydney, NSW, 2007, Australia.
⁶ National Breast Cancer Foundation Level 7, 50 Margaret Street, Sydney, NSW, 2001, Australia.
⁷ Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst Sydney, NSW, 2010, Australia. c.ormandy@garvan.org.au.
⁸ St. Vincent's Clinical School, St. Vincent's Hospital, UNSW Sydney, Kensington, NSW, Australia. c.ormandy@garvan.org.au.

^# Contributed equally.

Abstract

Background: The interferon response can influence the primary and metastatic activity of breast cancers and can interact with checkpoint immunotherapy to modulate its effects. Using N-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.

Methods: To determine if sole activation of Oas2 could alter the course of mammary cancer, we combined the Oas2 mutation with the MMTV-PyMT oncogene model of breast cancer and examined disease progression and the effects of checkpoint immunotherapy using Kaplan-Meier survival analysis with immunohistochemistry and flow cytometry.

Results: Oas2 mutation prevented pregnancy from increasing metastases to lung. Checkpoint immunotherapy with antibodies against programmed death-ligand 1 was more effective when the Oas2 mutation was present.

Conclusions: These data establish OAS2 as a therapeutic target for agents designed to reduce metastases and increase the effectiveness of checkpoint immunotherapy.

Keywords: Breast; Cancer; Immunotherapy; Interferon; Mammary; OAS2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

2',5'-Oligoadenylate Synthetase* / genetics
Adenine Nucleotides
Animals
Breast Neoplasms* / genetics
Female
Humans
Interferons
Ligases
Mice
Oligoribonucleotides
Pregnancy

Substances

Adenine Nucleotides
Oligoribonucleotides
2',5'-oligoadenylate
Interferons
2',5'-Oligoadenylate Synthetase
Ligases