Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas.
Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas.
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DOI：
10.1158/1078-0432.ccr-12-2091
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发表时间：
2013-04-01
期刊：
影响因子：
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通讯作者：
Kusmartsev S
中科院分区：
文献类型：
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作者：
Eruslanov E;Stoffs T;Kim WJ;Daurkin I;Gilbert SM;Su LM;Vieweg J;Daaka Y;Kusmartsev S
趋化因子参与癌症相关炎症和恶性进展。在这项研究中，我们评估了CCR8及其天然同源配体CCL1在膀胱和肾细胞癌患者尿路上皮癌中的表达。我们检测了膀胱癌和肾癌患者外周血和肿瘤组织中CCR8的表达。用磁珠从癌组织中分离出ccr8阳性骨髓细胞，并在体外测试细胞因子的产生和调节T细胞功能的能力。我们证明，尿路上皮癌和肾癌患者外周血单核细胞和粒细胞髓样细胞亚群显示趋化因子受体CCR8的表达增加。在人类癌症组织中也检测到CCR8的上调表达，并且主要局限于肿瘤相关巨噬细胞（tam）。当分离时，CD11b+CCR8+细胞亚群在肿瘤内CD11b骨髓细胞中产生最高水平的促炎症和促血管生成因子。肿瘤浸润的CD11b+CCR8+细胞选择性地显示活化的Stat3，并能够诱导自身T淋巴细胞中FoxP3的表达。原发性人类肿瘤产生大量的天然CCR8配体CCL1。本研究首次提供了CCR8+髓系细胞亚群在癌症患者中扩增的证据。肿瘤分泌CCL1升高，外周血和癌组织中CCR8+髓样细胞增加，表明CCL1/CCR8轴是癌症相关炎症的一个组成部分，可能有助于免疫逃避。获得的结果还表明，阻断CCR8信号可能为人类尿路上皮和肾癌的治疗干预提供了一种有吸引力的策略。
Chemokines are involved in cancer-related inflammation and malignant progression. In this study we evaluated expression of CCR8 and its natural cognate ligand CCL1 in patients with urothelial carcinomas of bladder and renal cell carcinomas. We examined CCR8 expression in peripheral blood and tumor tissues from patients with bladder and renal carcinomas. CCR8-positive myeloid cells were isolated from cancer tissues with magnetic beads and tested in vitro for cytokine production and ability to modulate T cell function. We demonstrate that monocytic and granulocytic myeloid cell subsets in peripheral blood of cancer patients with urothelial and renal carcinomas display increased expression of chemokine receptor CCR8. Up-regulated expression of CCR8 is also detected within human cancer tissues and primarily limited to tumor-associated macrophages (TAMs). When isolated, CD11b+CCR8+ cell subset produces the highest levels of pro-inflammatory and pro-angiogenic factors among intratumoral CD11b myeloid cells. Tumor-infiltrating CD11b+CCR8+ cells selectively display activated Stat3 and are capable of inducing FoxP3 expression in autologous T lymphocytes. Primary human tumors produce substantial amounts of the natural CCR8 ligand CCL1. This study provides the first evidence that CCR8+ myeloid cell subset is expanded in cancer patients. Elevated secretion of CCL1 by tumors, increased presence of CCR8+ myeloid cells in peripheral blood and cancer tissues indicate that CCL1/CCR8 axis is a component of cancer-related inflammation and may contribute to immune evasion. Obtained results also implicate that blockade of CCR8 signals may provide an attractive strategy for therapeutic intervention in human urothelial and renal cancers.