Myeloid activation clears ascites and reveals IL27-dependent regression of metastatic ovarian cancer
Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of <30% due to the persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of β-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. β-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa.
Authors
- Nan Zhang (ORCID: https://orcid.org/0000-0002-6736-2781)
- Yulia Nefedova (ORCID: https://orcid.org/0000-0002-5121-9294)
- Gauri Mirji (ORCID: https://orcid.org/0000-0001-6439-8204)
- Andrew V. Kossenkov (ORCID: https://orcid.org/0000-0002-1536-0418)
- Filippo Veglia (ORCID: https://orcid.org/0000-0001-6710-1584)
- Yanfang Peipei Zhu (ORCID: https://orcid.org/0000-0001-6908-0860)
- Lu Huang (ORCID: https://orcid.org/0000-0002-7820-2177)
- Rahul Shinde (ORCID: https://orcid.org/0000-0001-8767-5032)
- Taito Miyamoto (ORCID: https://orcid.org/0000-0001-7453-1611)
- Toshitha Kannan (ORCID: https://orcid.org/0009-0007-7775-6585)
- Daniel T. Claiborne (ORCID: https://orcid.org/0000-0002-2091-1456)
- Rugang Zhang (ORCID: https://orcid.org/0000-0002-7255-2360)
- Bryan Manning
- Alessio Ugolini (ORCID: https://orcid.org/0000-0002-5970-9693)
- Kohei Hamada (ORCID: https://orcid.org/0009-0003-0354-7722)
- Brennah Murphy (ORCID: https://orcid.org/0000-0003-3698-6513)
Institutions
- The Wistar Institute (US)
- The University of Texas MD Anderson Cancer Center (US)
- Kyoto University (JP)
- Augusta University (US)
- Saint Joseph's University (US)
- University of Arkansas for Medical Sciences (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1084/jem.20231967
- Citations
- 11
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.65
Funders
- U.S. Department of Defense
- W. W. Smith Charitable Trust
- University of Pennsylvania
- Johns Hopkins University
- National Institutes of Health
- Japan Society for the Promotion of Science
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Institute of Neurological Disorders and Stroke