PDF(Pubmed)
Abstract：
Inflammation is a hallmark of cancer1. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2-5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b+HLA-DRloCD15+CD14- myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.
摘要：
炎症是癌症的标志1。在癌症患者中，外周血髓样扩张，高中性粒细胞与淋巴细胞比率（NLR）表明，与恶性肿瘤和治疗模式之间的较短生存期和治疗耐药性相关2-5。骨髓性炎症是否驱动人类前列腺癌的进展仍不清楚。在本文中，我们表明，在转移性去势抵抗性前列腺癌（mCRPC）患者的一部分中，对髓样趋化的抑制可以减少肿瘤引起的髓样炎症和逆转治疗抵抗。我们表明，较高的血液NLR反映了肿瘤髓样浸润和衰老相关mRNA种类的肿瘤表达，包括髓样化学吸引CXCR2配体。为了确定骨髓细胞是否为雄激素受体信号传导抑制剂（ARSI）抵抗提供燃料，如果抑制CXCR2来阻断骨髓趋化性，我们进行了一个调查员发起的，CXCR2抑制剂（AZD5069）联合恩杂鲁胺治疗ARSI耐药mCRPC患者的概念验证临床试验。这种组合耐受性良好，没有剂量限制性毒性和减少循环中性粒细胞，肿瘤内CD11b+HLA-DRloCD15+CD14-骨髓细胞浸润减少，并在部分mCRPC患者中通过生化和放射学反应赋予持久的临床益处。这项研究提供了第一个临床证据，表明衰老相关的髓样炎症可以促进mCRPC进展和对AR阻断的抵抗。靶向骨髓趋化性值得在其他癌症中进行更广泛的评估。
