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Knockdown of the Prolactin Receptor Inhibits Recruitment of Tregs and their Promotion of EMT in a Syngeneic Breast Cancer Model

ABSTRACT: The clinical relevance and prognostic significance of tumor-infiltrating Tregs in different types of cancers makes them appealing therapeutic targets. However, while effective at inhibiting cancer progression, immunotherapeutics targeting Treg function have adverse effects in a substantial proportion of patients, ranging from mild inflammatory disorders to frank autoimmune disease. Here, we report that systemic knockdown of the long form of the prolactin receptor (LFPRLR) inhibits recruitment of Tregs to primary tumors and, importantly, metastasis-promoting activities of tumor Tregs, with no change in the production of TGFβ or IL-10 by tumor Tregs or the ability of peripheral Tregs to suppress anti-CD3/CD28-stimulated effector cell proliferation. Knockdown of the LFPRLR was accomplished using a derivatized DNA splice-modulating oligomer and outcome was assessed in the highly-metastatic, syngeneic, orthotopic 4T1-Balb/c immune-competent breast cancer model. We conclude that knockdown of the LFPRLR produces a more functionally-specific anti-cancer effect in Tregs, suggesting promise as a future therapeutic approach.

ORGANISM(S): Mus musculus

PROVIDER: GSE111329 | GEO | 2019/02/28

REPOSITORIES: GEO

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Knockdown of the Prolactin Receptor Inhibits Recruitment of Tregs and their Promotion of EMT in a Syngeneic Breast Cancer Model

Project description:Knockdown of the Prolactin Receptor Inhibits Recruitment of Tregs and their Promotion of EMT in a Syngeneic Breast Cancer Model

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Prolactin enhances T regulatory cell promotion of breast cancer through the long form prolactin receptor.

Project description:Previous work has shown systemic knockdown of the long form prolactin receptor (LFPRLR) in vivo markedly reduced metastasis in mouse models of breast cancer, but whether this translated to prolonged survival was unknown. Here we show that LFPRLR knockdown in the highly metastatic, immunocompetent 4T1 model prolonged survival and reduced recruitment of T regulatory cells (Tregs) to the tumor through effects on the production of CCL17. For the Tregs still recruited to the primary tumor, LFPRLR knockdown both directly and indirectly reduced their ability to promote tumor parenchymal epithelial to mesenchymal transition. Importantly, effects of prolactin on expression of mesenchymal genes by the tumor parenchyma were very different in the absence and presence of Tregs. While systemic knockdown of the LFPRLR downregulated transcripts important for immune synapse function in the remaining tumor Tregs, splenic Tregs seemed unaffected by LFPRLR knockdown, as demonstrated by their continued ability to suppress anti-CD3/CD28-stimulated effector cell proliferation at 1-5 months. These results demonstrate that knockdown of the LFPRLR achieves intra-tumor immunotherapeutic effects and suggest this occurs with reduced likelihood of peripheral inflammatory/autoimmune sequelae.

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Project description:Tumor-draining lymph node (TDLN) invasion by metastatic cells in breast cancer correlates with poor prognosis and is associated with local immunosuppression, which can be partly mediated by regulatory T cells (Tregs). Here, we study Tregs from matched tumor-invaded and non-invaded TDLNs, and breast tumors. We observe that Treg frequencies increase with nodal invasion, that Tregs express higher levels of co-inhibitory/stimulatory receptors than effector cells. Also, while Tregs show conserved suppressive function in TDLN and tumor, conventional T cells (Tconvs) in TDLNs proliferate and produce Th1-inflammatory cytokines, but are dysfunctional in the tumor. We describe a common transcriptomic signature shared by Tregs from tumors and nodes, including CD80, which is significantly associated with poor patient survival. TCR RNA-sequencing analysis indicates trafficking between TDLNs and tumors and ongoing Tconv/Treg conversion. Overall, TDLN Tregs are functional and express a distinct pattern of druggable co-receptors, highlighting their potential as targets for cancer immunotherapy.

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