前列腺癌（PCa）的骨转移性疾病是无法治愈的，骨的进展很大程度上取决于骨微环境中的肿瘤-基质相互作用。我们之前表明，骨中性粒细胞最初抑制骨转移性 PCa 生长，但转移性 PCa 对中性粒细胞反应产生抵抗。此外，从肿瘤骨中分离出的中性粒细胞失去了通过未知机制抑制肿瘤生长的能力。通过这项研究，我们的目标是确定转移性 PCa 在整个肿瘤进展过程中对中性粒细胞功能的影响，并确定中性粒细胞作为转移性疾病预测生物标志物的潜力。使用患者外周血多形核中性粒细胞 (PMN)，我们发现 PCa 进展决定 PMN 细胞表面标志物和基因表达，但不影响 PCa 的细胞毒性。重要的是，我们还发现了一种新现象，即第二代雄激素剥夺疗法 (ADT) 通过增加转化生长因子 β 受体 I (TβRI) 来抑制 PMN 细胞毒性。高剂量睾酮和遗传或药理 TβRI 抑制可挽救雄激素受体介导的中性粒细胞抑制并恢复中性粒细胞抗肿瘤免疫反应。这些研究强调了利用标准护理 ADT 产生针对骨转移性 PCa 的中性粒细胞抗肿瘤反应的能力。版权所有 © 2023。由 Elsevier B.V. 出版。

Bone metastatic disease of prostate cancer (PCa) is incurable and progression in bone is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that bone neutrophils initially inhibit bone metastatic PCa growth yet metastatic PCa becomes resistant to neutrophil response. Further, neutrophils isolated from tumor-bone lost their ability to suppress tumor growth through unknown mechanisms. With this study, our goal was to define the impact of metastatic PCa on neutrophil function throughout tumor progression and to determine the potential of neutrophils as predictive biomarkers of metastatic disease. Using patient peripheral blood polymorphonuclear neutrophils (PMNs), we identified that PCa progression dictates PMN cell surface markers and gene expression, but not cytotoxicity against PCa. Importantly, we also identified a novel phenomenon in which second generation androgen deprivation therapy (ADT) suppresses PMN cytotoxicity via increased transforming growth factor beta receptor I (TβRI). High dose testosterone and genetic or pharmacologic TβRI inhibition rescued androgen receptor-mediated neutrophil suppression and restored neutrophil anti-tumor immune response. These studies highlight the ability to leverage standard-care ADT to generate neutrophil anti-tumor responses against bone metastatic PCa.Copyright © 2023. Published by Elsevier B.V.