Phenotypic and Functional Delineation of Murine CX3CR1+ Monocyte-Derived Cells in Ovarian Cancer
Phenotypic and Functional Delineation of Murine CX3CR1+ Monocyte-Derived Cells in Ovarian Cancer
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DOI：
10.1593/neo.09228
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发表时间：
2009-06-01
期刊：
影响因子：
4.8
通讯作者：
Berwin, Brent
中科院分区：
文献类型：
--
作者：
Hart, Kevin M.;Bak, S. Peter;Berwin, Brent
卵巢肿瘤的进展以白细胞腹膜积聚为标志。在这些白细胞中，在人类和卵巢肿瘤中均发现了免疫抑制性 CD11b(+)CD11c(+) 群体。使用小鼠卵巢肿瘤可移植模型已证明该群体促进卵巢肿瘤生长，而消除该群体已被证明可抑制卵巢肿瘤进展。尽管这些细胞对卵巢肿瘤进展的重要性已被证明，但这些细胞被招募到腹膜肿瘤的机制在很大程度上尚不清楚。因此，本研究分析了这些细胞迁移到腹膜的机制，目的是治疗性阻断它们的募集和随后的免疫抑制活性。最近的研究发现 CX(3)CR1、Gr-1 和 CCR2 描绘了表型和功能性小鼠单核细胞亚群。在此，我们报告在小鼠肿瘤发展早期，CX(3)CR1(lo)Gr-1(hi)细胞在腹膜CD11b(+)白细胞群中占主导地位；然而，在肿瘤进展过程中，腹膜中存在的 CX(3)CR1(hi) 细胞群的总数和百分比均急剧增加。功能分析表明，这两个 CX3CR1 亚群对初始 CD8(+) 和 CD4(+) T 细胞反应具有免疫抑制作用。重要的是，我们证明CCR2是白细胞募集到卵巢肿瘤微环境的关键功能促进剂，与野生型小鼠相比，其基因缺失导致肿瘤负荷减少。这些结果表明，免疫抑制白细胞亚群通过 CCR2 途径被招募到卵巢肿瘤环境，这提供了抑制其迁移到肿瘤部位的可行治疗靶点。
Ovarian tumor progression is marked by the peritoneal accumulation of leukocytes. Among these leukocytes, an immunosuppressive CD11b(+)CD11c(+) population has been identified in both human and ovarian tumors. The use of transplantable models of murine ovarian tumors has demonstrated that this population promotes ovarian tumor growth, whereas elimination of this population has been shown to inhibit ovarian tumor progression. Despite the demonstrated importance of these cells to ovarian tumor progression, the mechanisms by which these cells are recruited to the peritoneal tumor are largely unknown. Therefore, this study analyzes the mechanisms these cells use to migrate to the peritoneum with the goal of therapeutically blocking their recruitment and subsequent immunosuppressive activity. Recent studies have identified that CX(3)CR1, Gr-1, and CCR2 delineate phenotypic and functional murine monocyte subsets. Here, we report that CX(3)CR1(lo)Gr-1(hi) cells dominate the population of peritoneal CD11b(+) leukocytes early in murine tumor development; however, the CX(3)CR1(hi) population of cells present in the peritoneum dramatically increases in both total numbers and percentage during tumor progression. Functional analyses reveal that both of these CX3CR1 subsets are immunosuppressive to naive CD8(+) and CD4(+) T-cell responses. Importantly, we demonstrate that CCR2 is a critical functional facilitator of leukocyte recruitment to the ovarian tumor microenvironment, and its genetic deletion results in a reduced tumor burden compared with wild-type mice. These results demonstrate that subsets of immunosuppressive leukocytes are recruited to the ovarian tumor environment through the CCR2 pathway, which offers a viable therapeutic target to inhibit their migration to the tumor site.