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000306275 1001_ $$aZorea, Jonathan$$b0
000306275 245__ $$aTRAF3 suppression encourages B cell recruitment and prolongs survival of microbiome-intact mice with ovarian cancer.
000306275 260__ $$aHeidelberg$$bSpringer$$c2023
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000306275 520__ $$aOvarian cancer (OC) is known for exhibiting low response rates to immune checkpoint inhibitors that activate T cells. However, immunotherapies that activate B cells have not yet been extensively explored and may be a potential target, as B cells that secrete immunoglobulins have been associated with better outcomes in OC. Although the secretion of immunoglobulins is often mediated by the microbiome, it is still unclear what role they play in limiting the progression of OC.We conducted an in-vivo CRISPR screen of immunodeficient (NSG) and immune-intact wild type (WT) C57/BL6 mice to identify tumor-derived immune-escape mechanisms in a BRAC1- and TP53-deficient murine ID8 OC cell line (designated ITB1). To confirm gene expression and signaling pathway activation in ITB1 cells, we employed western blot, qPCR, immunofluorescent staining, and flow cytometry. Flow cytometry was also used to identify immune cell populations in the peritoneum of ITB1-bearing mice. To determine the presence of IgA-coated bacteria in the peritoneum of ITB1-bearing mice and the ascites of OC patients, we employed 16S sequencing. Testing for differences was done by using Deseq2 test and two-way ANOVA test. Sequence variants (ASVs) were produced in Qiime2 and analyzed by microeco and phyloseq R packages.We identified tumor necrosis factor receptor-associated factor 3 (TRAF3) as a tumor-derived immune suppressive mediator in ITB1 cells. Knockout of TRAF3 (TRAF3KO) activated the type-I interferon pathway and increased MHC-I expression. TRAF3KO tumors exhibited a growth delay in WT mice vs. NSG mice, which was correlated with increased B cell infiltration and activation compared to ITB1 tumors. B cells were found to be involved in the progression of TRAF3KO tumors, and B-cell surface-bound and secreted IgA levels were significantly higher in the ascites of TRAF3KO tumors compared to ITB1. The presence of commensal microbiota was necessary for B-cell activation and for delaying the progression of TRAF3KO tumors in WT mice. Lastly, we observed unique profiles of IgA-coated bacteria in the ascites of OC-bearing mice or the ascites of OC patients.TRAF3 is a tumor-derived immune-suppressive modulator that influences B-cell infiltration and activation, making it a potential target for enhancing anti-tumor B-cell responses in OC.
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000306275 650_7 $$2Other$$aB cells
000306275 650_7 $$2Other$$aBRAC1-mutated ovarian cancer
000306275 650_7 $$2Other$$aIgA
000306275 650_7 $$2Other$$aMicrobiome
000306275 650_7 $$2Other$$aTRAF3
000306275 650_7 $$2NLM Chemicals$$aTNF Receptor-Associated Factor 3
000306275 650_7 $$2NLM Chemicals$$aImmunoglobulin A
000306275 650_7 $$2NLM Chemicals$$aTRAF3 protein, human
000306275 650_2 $$2MeSH$$aHumans
000306275 650_2 $$2MeSH$$aFemale
000306275 650_2 $$2MeSH$$aMice
000306275 650_2 $$2MeSH$$aAnimals
000306275 650_2 $$2MeSH$$aTNF Receptor-Associated Factor 3: genetics
000306275 650_2 $$2MeSH$$aTNF Receptor-Associated Factor 3: metabolism
000306275 650_2 $$2MeSH$$aAscites
000306275 650_2 $$2MeSH$$aMice, Knockout
000306275 650_2 $$2MeSH$$aOvarian Neoplasms: pathology
000306275 650_2 $$2MeSH$$aImmunoglobulin A: metabolism
000306275 650_2 $$2MeSH$$aCell Line, Tumor
000306275 7001_ $$aMotro, Yair$$b1
000306275 7001_ $$aMazor, Roei D$$b2
000306275 7001_ $$aCarmi, Yifat Koren$$b3
000306275 7001_ $$aShulman, Ziv$$b4
000306275 7001_ $$aMahajna, Jamal$$b5
000306275 7001_ $$aMoran-Gilad, Jacob$$b6
000306275 7001_ $$00000-0003-3634-9098$$aElkabets, Moshe$$b7
000306275 773__ $$0PERI:(DE-600)2430698-8$$a10.1186/s13046-023-02680-7$$gVol. 42, no. 1, p. 107$$n1$$p107$$tJournal of experimental & clinical cancer research$$v42$$x0392-9078$$y2023
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