Engagement of myelomonocytic Siglecs by tumor-associated ligands modulates the innate immune response to cancer
Engagement of myelomonocytic Siglecs by tumor-associated ligands modulates the innate immune response to cancer
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DOI：
10.1073/pnas.1409580111
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发表时间：
2014-09-30
影响因子：
11.1
通讯作者：
Varki, Ajit
中科院分区：
文献类型：
--
作者：
Laubli, Heinz;Pearce, Oliver M. T.;Varki, Ajit
已知某些病原性细菌通过用唾液酸修饰自身来调节先天性免疫应答，唾液酸可以接合骨髓单核细胞谱系抑制性受体Siglec-9，从而逃避免疫监视。我们假设，众所周知的上调唾液酸糖缀合物的肿瘤可能类似地调节与先天免疫细胞的相互作用。支持这一假设，在人肿瘤样品中发现的表达Siglec-9的骨髓单核细胞伴随着Siglec-9配体的强烈上调。Siglec-9的阻断增强了体外中性粒细胞对肿瘤细胞的活性。为了研究体内抑制性骨髓单核细胞Siglec的功能，我们研究了小鼠Siglec-E，Siglec-9的鼠功能等同物。Siglec-E缺陷型小鼠显示出增加的体内肿瘤细胞杀伤，并且这种作用通过骨髓单核细胞中的转基因Siglec-9表达而逆转。Siglec-E缺陷型小鼠也表现出增强的自体肿瘤免疫监视。然而，一旦肿瘤建立，它们在Siglec-E缺陷小鼠中生长得更快。与此一致，Siglec-E缺陷型巨噬细胞显示出肿瘤促进M2极化的倾向，表明CD 33相关Siglecs在限制癌症促进炎症和肿瘤生长中的次要作用。因此，我们定义了抑制性骨髓单核细胞Siglecs在癌症生物学中的先前未识别的影响，其具有反映骨髓单核细胞在癌症进展中的双重功能的不同作用。与此一致，减少Siglec-9与癌症结合的人类多态性与非小细胞肺癌患者的早期生存期改善相关，这表明Siglec-9可能在正确的时间框架和疾病阶段内成为治疗靶点。
Certain pathogenic bacteria are known to modulate the innate immune response by decorating themselves with sialic acids, which can engage the myelomonocytic lineage inhibitory receptor Siglec-9, thereby evading immunosurveillance. We hypothesized that the well-known up-regulation of sialoglycoconjugates by tumors might similarly modulate interactions with innate immune cells. Supporting this hypothesis, Siglec-9-expressing myelomonocytic cells found in human tumor samples were accompanied by a strong up-regulation of Siglec-9 ligands. Blockade of Siglec-9 enhanced neutrophil activity against tumor cells in vitro. To investigate the function of inhibitory myelomonocytic Siglecs in vivo we studied mouse Siglec-E, the murine functional equivalent of Siglec-9. Siglec-E-deficient mice showed increased in vivo killing of tumor cells, and this effect was reversed by transgenic Siglec-9 expression in myelomonocytic cells. Siglec-E-deficient mice also showed enhanced immunosurveillance of autologous tumors. However, once tumors were established, they grew faster in Siglec-E-deficient mice. In keeping with this, Siglec-E-deficient macrophages showed a propensity toward a tumor-promoting M2 polarization, indicating a secondary role of CD33-related Siglecs in limiting cancer-promoting inflammation and tumor growth. Thus, we define a previously unidentified impact of inhibitory myelomonocytic Siglecs in cancer biology, with distinct roles that reflect the dual function of myelomonocytic cells in cancer progression. In keeping with this, a human polymorphism that reduced Siglec-9 binding to carcinomas was associated with improved early survival in non-small- cell lung cancer patients, which suggests that Siglec-9 might be therapeutically targeted within the right time frame and stage of disease.