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BackgroundOvarian cancer (OvCa) is the most lethal gynecological cancer and the fifth leading cause of cancer-related deaths in women. Despite an initial positive response to therapy, most patients relapse and present with chemotherapy resistance. The prognosis for recurrent disease is poor, with a 5-year survival rate of < 30%. One contributor to disease recurrence and therapy resistance is the presence of disseminated cancer cells that remain in the peritoneal fluid after treatment. A growing body of evidence suggests that these cells exhibit dormancy characteristics that render them resistant to most therapies. Moreover, cancer cells in fluid are unable to be surgically resected. Because 75% of relapsed patients present with therapy-resistant intraperitoneal disease, developing new strategies to effectively target disseminating OvCa cells in the peritoneal fluid is crucial for the effective treatment of OvCa. Two key players in peritoneal immunity, the omentum and peritoneal resident macrophages (PRMΦs), are known to sequester pathogens in the peritoneal fluid and coordinate an inflammatory immune response in the peritoneum. One such activator of peritoneal immunity is β-glucan, a sugar found on the cell walls of yeasts.ObjectiveTo target disseminating OvCa cells in the peritoneal fluid by activating myeloid cells in the peritoneal cavity via intraperitoneal administration of β-glucan.MethodsC57bl/6J mice were injected with GFP-labeled murine OvCa cells (KPCA: Trp53 −/−R172H Ccne1 OE Akt2 OE KRAS G12V) immediately followed by 500μg β-glucan (i.p.). Five hours later, mice were euthanized and their peritoneal lavage was analyzed for the presence of OvCa cells. To model advanced disease, Luciferase-KPCA cells were seeded in C57bl/6J mice one week prior to biweekly β-glucan treatment and imaged 3 weeks later.ResultsFirst, we found that β-glucan was highly efficient in acutely clearing OvCa cells from the peritoneal fluid. Mechanistically, β-glucan captured free-floating OvCa cells into solid nodules through two non-redundant and equally important pathways: (1) an unexpected Dectin-1/SYK-independent, heparin-sensitive pathway that was mediated by PRMΦ aggregation in the peritoneal fluid; and (2) a Dectin-1/SYK/PAD4-dependent pathway that was mediated by neutrophil extracellular traps in the omentum. Second, we found that β-glucan also completely cleared cancer from the peritoneal fluid and prevented ascites accumulation in advanced disease. Combining β-glucan with IFNγ (β-glucan/IFNγ) not only cleared ascites but also regressed omentum tumors and prevented intraperitoneal metastases as compared to PBS-, β-glucan-, or IFNγ-treated mice.ConclusionsIntraperitoneal injection of β-glucan clears OvCa cells from the peritoneal fluid and has therapeutic potential to control OvCa metastasis.

BackgroundEradication 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.MethodsRecently 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) γ 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. IFNγ 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 IFNγ. Furthermore, OC patient survival was analyzed based on gene expression using public dataset. Finally, combination of myeloid cell activation with carboplatin was tested.Resultsβ-glucan alone was efficient in clearing ascites, although it did not affect total metastases. On the other hand, combining β-glucan with IFNγ (β-glucan/IFNγ) not only cleared ascites but also reduced total metastases compared to PBS-, β-glucan-, or IFNγ-treated mice. This anti-tumor immunity required T cells and non-tumor IFNγ signaling in the host. scRNA seq of omental tumors revealed β-glucan/IFNγ 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/IFNγ. OC patients with high expression of these genes identified in the novel myeloid cell subsets correlate with better overall survival. Finally, combining β-glucan/IFNγ with carboplatin nearly eradicated chemoresistant KPCA tumors.Conclusionsβ-glucan/IFNγ 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 ApprovalThis study is approved by IACUC (#201536).

Children and adults with Philadelphia chromosome-like B cell acute lymphoblastic leukemia (Ph-like B-ALL) experience high relapse rates despite best-available conventional chemotherapy. Ph-like ALL is driven by genetic alterations that activate constitutive cytokine receptor and kinase signaling, and early-phase trials are investigating the potential of the addition of tyrosine kinase inhibitors (TKIs) to chemotherapy to improve clinical outcomes. However, preclinical studies have shown that JAK or PI3K pathway inhibition is insufficient to eradicate the most common cytokine receptor-like factor 2-rearranged (CRLF2-rearranged) Ph-like ALL subset. We thus sought to define additional essential signaling pathways required in Ph-like leukemogenesis for improved therapeutic targeting. Herein, we describe an adaptive signaling plasticity of CRLF2-rearranged Ph-like ALL following selective TKI pressure, which occurs in the absence of genetic mutations. Interestingly, we observed that Ph-like ALL cells have activated SRC, ERK, and PI3K signaling consistent with activated B cell receptor (BCR) signaling, although they do not express cell surface μ-heavy chain (μHC). Combinatorial targeting of JAK/STAT, PI3K, and \"BCR-like\" signaling with multiple TKIs and/or dexamethasone prevented this signaling plasticity and induced complete cell death, demonstrating a more optimal and clinically pragmatic therapeutic strategy for CRLF2-rearranged Ph-like ALL.

Internal tandem duplication mutations in fms-like tyrosine kinase 3 ( FLT3-ITD ) are recurrent in acute myeloid leukemia (AML) and increase the risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) include myeloid differentiation of the FLT3 - ITD clone in nearly half of patients through an unknown mechanism. We identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this effect using a proteomic-based screen. FLT3i downregulated EZH2 protein expression and PRC2 activity on H3K27me3. FLT3-ITD and loss-of-function mutations in EZH2 are mutually exclusive in human AML. We demonstrated that FLT3i increase myeloid maturation with reduced stem/progenitor cell populations in murine Flt3-ITD AML. Combining EZH1/2 inhibitors with FLT3i increased terminal maturation of leukemic cells and reduced leukemic burden. Our data suggest that reduced EZH2 activity following FLT3 inhibition promotes myeloid differentiation of FLT3-ITD leukemic cells, providing a mechanistic explanation for the clinical observations. These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for FLT3-ITD AML.

Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of less than 30% due to 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 . 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.

Germany and Italy declare war on the United States, following the Americans' declaration of war on the Empire of Japan in the wake of the attack on Pearl Harbor.

In San Francisco, California, city mayor George Moscone and the first openly gay man elected to public office in the United States, Harvey Milk, were assassinated by former supervisor Dan White.

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