Department of Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Box 435, 405 30, Göteborg, Sweden,
Cancer Immunol Immunother. 2013 Nov;62(11):1687-95. doi: 10.1007/s00262-013-1472-0. Epub 2013 Sep 8.
Recruitment of immune cells to tumors is a complex process crucial for both inflammation-driven tumor progression and specific anti-tumor cytotoxicity. Chemokines control the directed migration of immune cells, and their actions are partly controlled by nonsignaling chemokine decoy receptors. The role of the receptors such as D6, Duffy antigen receptor for chemokines and ChemoCentryx chemokine receptor in immunity to tumors is still unclear. Using real-time PCR, we detected significantly decreased expression of D6 mRNA in colon tumors compared to unaffected mucosa. D6 protein was expressed by lymphatic endothelium and mononuclear cells in the colon lamina propria and detected by immunohistochemistry in two out of six tissue samples containing high D6 mRNA levels, whereas no staining was observed in any tissue samples expressing low mRNA levels. When examining the density of lymphatic vessels in colon tumors, we detected a marked increase in vessels identified by the lymphatic endothelial marker Lyve-1, excluding passive regulation of D6 due to decreased lymphatic vessel density. In parallel, the Treg-recruiting chemokine CCL22, which is sequestered by D6, was threefold increased in tumor tissue. Furthermore, we could show that low D6 expression correlated to more invasive tumors and that tumor location influences D6 expression, which is lower in the more distal parts of the colon. The data support that regulation of D6 by colon tumors results in altered levels of proinflammatory CC chemokines, thereby shaping the local chemokine network to favor tumor survival. This may have implications for the design of future immunotherapy for colon cancer.
免疫细胞向肿瘤的募集是一个复杂的过程，对炎症驱动的肿瘤进展和特异性抗肿瘤细胞毒性都至关重要。趋化因子控制免疫细胞的定向迁移，其作用部分受非信号转导趋化因子诱饵受体控制。受体如 D6、趋化因子 Duffy 受体和 ChemoCentryx 趋化因子受体在肿瘤免疫中的作用仍不清楚。我们通过实时 PCR 检测到与未受影响的黏膜相比，结肠肿瘤中 D6mRNA 的表达明显降低。D6 蛋白在结肠固有层的淋巴管内皮细胞和单核细胞中表达，并通过免疫组织化学在 6 个含有高 D6mRNA 水平的组织样本中的 2 个样本中检测到，而在任何表达低 mRNA 水平的组织样本中均未观察到染色。当检查结肠肿瘤中淋巴管的密度时，我们检测到 Lyve-1 标记的淋巴管内皮细胞识别的血管明显增加，排除了由于淋巴管密度降低导致 D6 被动调节。与此同时，D6 可结合的 Treg 募集趋化因子 CCL22 在肿瘤组织中增加了三倍。此外，我们可以证明 D6 表达水平低与侵袭性更强的肿瘤相关，并且肿瘤位置影响 D6 的表达，在结肠的远端部分表达水平更低。这些数据支持结肠肿瘤对 D6 的调节导致促炎 CC 趋化因子水平发生改变，从而塑造有利于肿瘤存活的局部趋化因子网络。这可能对结肠癌的未来免疫治疗设计具有重要意义。
