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

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 TGFß 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. Overall design: mice were orthotopically injected with 4T1 breast cancer cells treated with other control splice modulating oligomer or LFPRLR splice modulating oligomer for 12 days. Whole tumor or sorted tumor Tregs were collected and the gene expression was analyzed by RNAseq between the control and LFPRLR treated mice. N=6 in each group.