BackgroundIn Ireland, every animal is examined at slaughter for its fitness for human consumption. The aim of this study was to determine the relative effectiveness of factories in submitting and subsequently in having suspect lesions confirmed as bovine tuberculosis (TB) lesions during the years 2005-2007. This work provides an update from previously published data for years 2003-2004. During 2005-2007 data were available on 4,401,813 cattle from attested herds (i.e. herds classified free of bovine TB), from which data for potential confounding factors were available for 3,344,057 slaughtered animals at one of the 37 export-licensed factories.FindingsFrom these animals, 8,178 suspect lesions were submitted for laboratory confirmation. Lesions from 5,456 (66.7%) animals tested as positive, and 269 (3.2%) were inconclusive for bovine TB. Logistic regression was used to determine adjusted submission and confirmation risks for each factory while controlling for confounding factors. Factory rankings based on adjusted and crude risks were similar. The average crude submission risk for all the factories was 25 lesions per 10,000 animals slaughtered, ranging from 0 to 52. The crude confirmation risk varied between 30.3% and 91.3%.ConclusionsSubstantial variation in the effectiveness of lesion submission and subsequent confirmation as bovine TB was found among the 37 factories. Compared to previous years (2003-2004), there was an increased bovine TB lesion submission and confirmation risk. Continued monitoring of the effectiveness of slaughter surveillance in Ireland is recommended; emphasis should be placed on efforts to improve bovine TB surveillance in factories with lower rankings.

Clinical efficacy of immune checkpoint therapy in high-grade serous carcinoma (HGSC) has been disappointing to date and highlights the need to better understand the relationship between HGSC and its associated immune microenvironment. Tractable model systems for interrogating the tumor microenvironment in HGSC could be used to address this unmet need. We have generated genetically engineered mouse models (GEMMs) of HGSC utilizing oviduct-restricted tamoxifen-regulated Cre recombinase to drive conditional inactivation of key tumor suppressor genes (Brca1, Trp53, Rb1, Nf1) observed to be recurrently altered in human HGSC samples. These autochthonous tumors arise from the murine fallopian tube (oviduct) in the context of an intact immune system. We employed RNA sequencing (RNA-seq) of bulk tumors from 19 mouse HGSCs to compare their gene expression profiles to those of normal oviduct and ovary tissues (4 each), and 6 mouse endometrioid-like oviductal carcinomas based on conditional inactivation of Apc and Pten. We employed immunogenomic analysis of the RNA-seq data to characterize the intratumoral infiltrate of 28 immune cell types in these samples in silico. The analysis revealed a prevalence of gene expression signatures associated with immunosuppressive cell types, including myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the mouse HGSCs, not observed in the other sample groups. Human HGSCs with available RNA-seq data (from TCGA samples) showed similar enrichment of MDSC and Treg gene signatures in the subset of human HGSCs classified as mesenchymal or immunoreactive expression subtypes. To further validate the findings in the mouse HGSCs, we used immunohistochemistry to detect subsets of tumor-infiltrating lymphocytes (TILs) in the tumor tissues. Specifically, CD8+ TIL infiltrates recapitulated epithelial (E-TIL), stromal (S-TIL) and combined epithelial/stromal (ES-TIL) patterns described in human HGSCs. Moreover, FoxP3+ Tregs were frequently observed to be co-infiltrated with CD8+ TILs as expected in an immunosuppressive tumor microenvironment. Gene set enrichment analysis showed that NF-kappa B signaling is among the top five pathways upregulated in HGSCs versus normal oviducts, suggesting a plausible mechanism by which tumor cells can alter and respond to the microenvironment during tumor development. These studies provide an experimental paradigm for improving our understanding of the role of the tumor microenvironment in HGSC pathogenesis and may aid in efforts to enhance the efficacy of immunotherapies in this lethal disease. Citation Format: Kevin W. McCool, Rork Kuick, Yali Zhai, Zach Freeman, Rong Wu, Eric Fearon, Kathleen R. Cho. Defining the tumor immune landscape in a mouse model of high-grade serous carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B65.

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