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首页> 美国卫生研究院文献>other >Tumor-Associated Disialylated Glycosphingolipid Antigen-Revealing Antibodies Found in Melanoma Patients Immunoglobulin Repertoire Suggest a Two-Direction Regulation Mechanism Between Immune B Cells and the Tumor
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Tumor-Associated Disialylated Glycosphingolipid Antigen-Revealing Antibodies Found in Melanoma Patients Immunoglobulin Repertoire Suggest a Two-Direction Regulation Mechanism Between Immune B Cells and the Tumor

机译：在黑素瘤患者的免疫球蛋白库中发现的肿瘤相关的二唾液酸化糖鞘脂抗原揭示抗体表明免疫B细胞和肿瘤之间的双向调节机制。

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There is far less information available about the tumor infiltrating B (TIL-B) cells, than about the tumor infiltrating T cells. We focused on discovering the features and potential role of B lymphocytes in solid tumors. Our project aimed to develop innovative strategies to define cancer membrane structures. We chose two solid tumor types, with variable to considerable B cell infiltration. The strategy we set up with invasive breast carcinoma, showing medullary features, has been introduced and standardized in metastatic melanoma. After detecting B lymphocytes by immunohistochemistry, VH-JH, Vκ-Jκ immunoglobulin rearranged V region genes were amplified by RT-PCR, from TIL-B cDNA. Immunoglobulin variable-region genes of interest were cloned, sequenced, and subjected to a comparative DNA analysis. Single-chain variable (scFv) antibody construction was performed in selected cases to generate a scFv library and to test tumor binding capacity. DNA sequence analysis revealed an overrepresented VH3-1 cluster, represented both in the breast cancer and the melanoma TIL-B immunoglobulin repertoire. We observed that our previously defined anti GD3 ganglioside-binder antibody-variable region genes were present in melanoma as well. Our antibody fragments showed binding potential to disialylated glycosphingolipids (GD3 ganglioside) and their O acetylated forms on melanoma cancer cells. We conclude that our results have a considerable tumor immunological impact, as they reveal the power of TIL-B cells to recognize strong tumor-associated glycosphingolipid structures on melanomas and other solid tumors. As tumor-derived gangliosides affect immune cell functions and reduce the B lymphocytes' antibody production, we suspect an important B lymphocyte and cancer cell crosstalk mechanism. We not only described the isolation and specificity testing of the tumor infiltrating B cells, but also showed the TIL-B cells' highly tumor-associated GD3 ganglioside-revealing potential in melanomas. The present data help to identify new cancer-associated biomarkers that may serve for novel cancer diagnostics. The two-direction regulation mechanism between immune B cells and the tumor could eventually be developed into an innovative cancer treatment strategy.
机译：关于肿瘤浸润性B（TIL-B）细胞的信息远远少于关于肿瘤浸润性T细胞的信息。我们着重于发现B淋巴细胞在实体瘤中的特征和潜在作用。我们的项目旨在开发创新策略来定义癌细胞膜结构。我们选择了两种实体瘤类型，B细胞浸润​​程度不同。我们针对转移性黑素瘤引入了具有髓样特征的浸润性乳腺癌，并对其进行了标准化。通过免疫组织化学检测到B淋巴细胞后，通过RT-PCR从TIL-B cDNA中扩增出VH-JH，Vκ-Jκ免疫球蛋白重排的V区基因。感兴趣的免疫球蛋白可变区基因被克隆，测序并进行了比较DNA分析。在选定的情况下进行单链可变（scFv）抗体构建，以生成scFv文库并测试肿瘤结合能力。 DNA序列分析显示，在乳腺癌和黑色素瘤TIL-B免疫球蛋白库中均存在过高表达的VH3-1簇。我们观察到我们先前定义的抗GD3神经节苷脂-粘合剂抗体可变区基因也存在于黑色素瘤中。我们的抗体片段在黑素瘤癌细胞上显示出与二唾液酸化糖鞘脂（GD3神经节苷脂）及其O乙酰化形式的结合潜力。我们得出的结论是，我们的结果具有相当大的肿瘤免疫学影响，因为它们揭示了TIL-B细胞能够识别黑色素瘤和其他实体瘤上与肿瘤相关的强糖鞘脂结构的强大功能。由于肿瘤神经节苷脂影响免疫细胞功能并降低B淋巴细胞的抗体生成，我们怀疑B淋巴细胞和癌细胞的重要串扰机制。我们不仅描述了肿瘤浸润性B细胞的分离和特异性测试，而且还显示了TIL-B细胞在黑素瘤中高度与肿瘤相关的GD3神经节苷脂暴露潜力。本数据有助于鉴定可能用于新型癌症诊断的新的癌症相关生物标记。免疫B细胞和肿瘤之间的双向调节机制最终可以发展成为一种创新的癌症治疗策略。

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