AI Summary
Researchers have developed a novel immunotherapy that activates myeloid cells to eradicate metastatic ovarian cancer (OC). Using β-glucan and interferon (IFN), the study found that combining these treatments cleared ascites and reduced total metastases in mice. This therapy required T cells and non-tumor IFN signaling in the host. The activation of myeloid cells led to the enrichment of neutrophils and macrophages with anti-tumor functions. Patients with high expression of the genes identified in these myeloid cell subsets showed better overall survival. Combining this therapy with chemotherapy could potentially transform the treatment of metastatic OC.
Background
Eradication of intraperitoneal metastasis of ovarian cancer (OC) remains an unmet challenge. Current T cell-mediating immunotherapies have not been applied to OC due to lack of efficacy in most patients. Immunosuppressive myeloid cells associate with tumor progression and treatment resistance in the metastatic sites of OC. The purpose of this study is to develop a novel immunotherapy that activates myeloid cells with the goal of eradicating metastatic OC.
Methods
Recently established, clinically relevant murine OC cells, that are homologous recombination proficient, KPCA (KRASG12VTrp53R172HCcne1OEAkt2OE ), were intraperitoneally injected to build the murine metastatic OC model. β-glucan and interferon (IFN) were used to activate myeloid cells. β-glucan is a yeast cell wall polysaccharide that is currently in clinical trials to treat multiple cancers. It canonically activates myeloid cells through the Dectin-1 pathway and induces infiltration of monocytes and neutrophils. IFN activates macrophages to an anti-tumor status. Tumor burden and tumor microenvironment in the ascites and omentum were evaluated using bioluminescence imaging, confocal imaging, flow cytometry, and single-cell RNA sequencing (scRNA seq) to investigate whether and how β-glucan modulates metastatic OC with or without IFN. Furthermore, OC patient survival was analyzed based on gene expression using public dataset. Finally, combination of myeloid cell activation with carboplatin was tested.
Results
β-glucan alone was efficient in clearing ascites, although it did not affect total metastases. On the other hand, combining β-glucan with IFN (β-glucan/IFN) not only cleared ascites but also reduced total metastases compared to PBS-, β-glucan-, or IFN-treated mice. This anti-tumor immunity required T cells and non-tumor IFN signaling in the host. scRNA seq of omental tumors revealed β-glucan/IFN induced the enrichment of a unique subset of neutrophils and macrophages compared to other groups. The neutrophil subset upregulated Camp and Ltf, which are granule proteins known to have tumoricidal function. Eukaryotic initiation factor-2 signaling, which is associated with reactive oxygen species (ROS) production, is the most upregulated pathway in the neutrophil subset. The macrophage subset selectively expressed interleukin (IL)-27, which has anti-tumor potential mainly through T cells. Blocking IL-27 significantly impaired the anti-tumor response of β-glucan/IFN. OC patients with high expression of these genes identified in the novel myeloid cell subsets correlate with better overall survival. Finally, combining β-glucan/IFN with carboplatin nearly eradicated chemoresistant KPCA tumors.
Conclusions
β-glucan/IFN suppressed metastatic OC enriching anti-tumor myeloid cell populations. Combination therapy of this myeloid cell activation and standard-of-care chemotherapy could potentially transform treatments against metastatic OC.
Ethics Approval
This study is approved by IACUC (#201536).