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.

以前的工作表明体内长型催乳素受体 (LFPRLR) 的系统性敲低乳腺癌小鼠模型中的转移显着减少，但这是否转化为延长生存期尚不清楚。在这里，我们显示在高转移性、免疫活性 4T1 模型中敲低 LFPRLR 通过影响 CCL17 的产生延长了生存期并减少了 T 调节细胞 (Tregs) 向肿瘤的募集。对于仍然招募到原发性肿瘤的 Treg，LFPRLR 敲低直接和间接降低了它们促进肿瘤实质上皮向间质转化的能力。重要的是，催乳素对肿瘤实质间充质基因表达的影响在 Treg 缺失和存在的情况下非常不同。虽然 LFPRLR 的系统性敲低下调了对剩余肿瘤 Treg 中的免疫突触功能很重要的转录物，脾脏 Tregs 似乎不受 LFPRLR 敲低的影响，正如它们在 1-5 个月时持续抑制抗 CD3/CD28 刺激的效应细胞增殖的能力所证明的那样。这些结果表明 LFPRLR 的敲低实现了肿瘤内免疫治疗效果，并表明这会随着外周炎症/自身免疫后遗症的可能性降低而发生。