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去势介导的IL-8促进骨髓浸润和前列腺癌进展

原文发布日期：2021-07-19

英文摘要：

摘要翻译：

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去势介导的IL-8促进骨髓浸润和前列腺癌进展

Castration-mediated IL-8 promotes myeloid infiltration and prostate cancer progression

原文发布日期：2021-07-19

英文摘要：

Unlike several other tumor types, prostate cancer rarely responds to immune checkpoint blockade (ICB). To define tumor cell intrinsic factors that contribute to prostate cancer progression and resistance to ICB, we analyzed prostate cancer epithelial cells from castration-sensitive and -resistant samples using implanted tumors, cell lines, transgenic models and human tissue. We found that castration resulted in increased expression of interleukin-8 (IL-8) and its probable murine homolog Cxcl15 in prostate epithelial cells. We showed that these chemokines drove subsequent intratumoral infiltration of tumor-promoting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which was largely abrogated when IL-8 signaling was blocked genetically or pharmacologically. Targeting IL-8 signaling in combination with ICB delayed the onset of castration resistance and increased the density of polyfunctional CD8 T cells in tumors. Our findings establish a novel mechanism by which castration mediates IL-8 secretion and subsequent PMN-MDSC infiltration, and highlight blockade of the IL-8/CXCR2 axis as a potential therapeutic intervention.

摘要翻译：

与几种其他类型的肿瘤相比，前列腺癌对免疫检查点阻断治疗 (ICB) 的反应率较低。为了找出促进前列腺癌进展和耐受 ICB 的原发性肿瘤细胞因素，我们分析了从 castration-sensitive 和 castration-resistant 样本中提取的前列腺上皮细胞，利用嵌入肿瘤、细胞系、转基因模型以及人组织进行了深入研究。我们发现，雄激素剥夺导致前列腺上皮细胞中原有的促炎因子如促炎小分子白细胞介素-8 (IL-8) 及其在小鼠中的同源体 Cxcl15 表达量显著增加。我们证实了这些促炎因子驱动肿瘤内部的后续浸润作用，这种作用在 IL-8 的信号通路被遗传性或药物性阻断后基本丧失。通过同时靶向 IL-8 信号通路及 ICB 治疗，我们延迟了前列腺癌对雄激素剥夺治疗的耐药性出现，并且增强了肿瘤中多功能 CD8 T 细胞的密度。我们的研究发现了雄激素剥夺通过促进 IL-8 的分泌及其后续 PMN-MDSC 的浸润这一全新机制，并突出了靶向 ILC-8 信号通路作为潜在治疗方法的意义。