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Comparative profiling of metastatic 4T1- versus non-metastatic Py230-based mammary tumors in an intraductal model for triple-negative breast cancer.

ABSTRACT: Purpose: Compare the tumor outgrowth and immunology of an immunocompetent 4T1- and Py230-based intraductal model for triple-negative breast cancer (TNBC). Methods: BALB/c-derived 4T1 and C57BL/6-derived Py230 mammary tumor cells were side-by-side intraductally inoculated in lactating and syngeneic mice, 4T1 and Py230 primary tumors were subsequently resected at 1, 3 and 6 weeks (w) post-inoculation (p.i.), and RNA was isolated from the 4T1 and Py230 primary tumors using in house developed protocols. Results: The differentially expressed genes in the 4T1 versus Py230 primary tumor datasets at the 3 different time points were categorized into 28 hallmark gene sets using GSEA. Nine hallmarks could be related to tumor immunology and collectively showed a decreased difference in expression over time, although every immunology-related gene set remained most expressed in 4T1 primary tumors across all time points. Seven hallmarks could be related to cellular mitosis and tumor progression and were significantly upregulated at 1 w p.i. in 4T1 primary tumors, whereas at 3 w p.i. they became significantly upregulated in Py230 primary tumors, indicative for enhanced Py230 tumor proliferation. The hallmark epithelial-mesenchymal transition was significantly upregulated at 3 w p.i. in 4T1 compared to Py230 primary tumors, indicative for metastatic progression. Gene sets involved in adipose/stromal processes within the mammary gland were downregulated or weakly expressed at 1 w p.i., but became upregulated at 3 w p.i. in 4T1 compared to Py230 primary tumors, indicating that at the time 4T1 tumor cells were less proliferative compared to Py230 tumor cells, the surrounding stroma and fat tissue were more active in the 4T1- compared to the Py230-based intraductal model. The hallmark androgen response also showed a significantly upregulated expression in Py230 tumors at 3 and 6 w p.i., indicating that androgen signaling is important in invasive Py230 tumors. Conclusion: Our findings highlight an innovative 4T1- and Py230-based intraductal mouse model for TNBC with a different tumor outgrowth and associated tumor microenvironment. These differential models may broadly represent the clinically observed TNBC diversity and together provide a powerful tool to evaluate therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE140192 | GEO | 2019/11/20

REPOSITORIES: GEO

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Project description:Purpose: Evaluate the anti-tumorigenic efficacy and immunomodulatory effects of chitin as general blocker of immunosuppressive chitinase-like proteins (CLPs) in combination with and without anti-PD-1 immune checkpoint blockade (ICB) in an immunocompetent 4T1- and 66cl4-based intraductal model for triple-negative breast cancer (TNBC). Methods: 4T1 and 66cl4 mammary tumor-bearing female BALB/c mice were either left untreated or were treated with anti-PD-1, chitin or chitin + anti-PD-1 for 2 weeks (w) between 3 and 5 w post-inoculation (p.i.) of the mammary tumor cells. After the 2-w treatment, 4T1 and 66cl4 primary tumors were resected and RNA was isolated from the tissue using in-house developed protocols. Results: Chitin-mediated reduction in innate immunosuppression and increased anti-tumor T-cell immunity in primary tumors of both TNBC models was clearly presented at the genomic level based on RNA-sequencing analysis. More specifically, a selection of 68 and 55 innate immunity-related genes in respectively 4T1 and 66cl4 primary tumors were downregulated upon chitin treatment in combination with or without anti-PD-1. Several of the selected innate immunity genes could be linked to immunosuppressive myeloid cell types, including Ccl2, Cxcl2, Csf1r and Itgam. Genes related to T-cell exhaustion, including Pdcd1, Cd274, Havcr2 and Lag3, were downregulated upon chitin and chitin + anti-PD-1 treatment in 4T1 tumors. Chitin- and chitin + anti-PD-1-treated 66cl4 tumors showed upregulation of genes associated with enhanced T-cell activity, including Cd8a, Cd8b1, Ifng, Il12b and Il18r1. In line with an overall reduced inflammation upon chitin treatment at the protein level, predominantly through myeloid cell reduction, a selected set of 68 and 48 inflammation-related genes were downregulated in chitin- and chitin + anti-PD-1-treated primary tumors of respectively the 4T1- and the 66cl4-based model. Importantly, genes that have been associated with the signaling and pro-tumorigenic activity of a prominent CLP family member, i.e. CHI3L1, were also downregulated in primary tumors following chitin treatment either with or without anti-PD-1, including Usf1 and Rab37 in the 4T1-based model and Lgals3 in the 66cl4-based model. Conclusion: Our findings highlight that chitin, as a general CLP blocker, reduces cancer-associated immunosuppression and enhances anti-tumor immunity as well as ICB responses in complementary ICB-resistant TNBC models, supporting its potential clinical relevance in immunosuppressed TNBC patients.

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Comparative profiling of metastatic 4T1- versus non-metastatic Py230-based mammary tumors in an intraductal model for triple-negative breast cancer.

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