Novel B7-H4-mediated crosstalk between human non-Hodgkin lymphoma cells and tumor-associated macrophages leads to immune evasion via secretion of IL-6 and IL-10
Novel B7-H4-mediated crosstalk between human non-Hodgkin lymphoma cells and tumor-associated macrophages leads to immune evasion via secretion of IL-6 and IL-10
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人类非霍奇金淋巴瘤细胞和肿瘤相关巨噬细胞之间新型 B7-H4 介导的串扰通过分泌 IL-6 和 IL-10 导致免疫逃避
DOI：
10.1007/s00262-017-1961-7
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发表时间：
2017-06-01
影响因子：
5.8
通讯作者：
Wang, Lijuan
中科院分区：
文献类型：
--
作者：
Che, Fengyuan;Heng, Xueyuan;Wang, Lijuan
非霍奇金淋巴瘤(NHL)是一种无法治愈的淋巴增生性癌症，患者预后较差。本研究探讨了免疫抑制B7-H4分子在人类非霍奇金淋巴瘤中的表达调控机制及其可能的作用。在功能研究方面，通过分离健康供者的同种异体CD3(+)T细胞，并用从患者分离的照射后的NHL细胞重复体外刺激，建立NHL反应性T细胞系。发现B7-H4分布于NHL细胞和组织中，其表面蛋白表达水平在NHL细胞与IL-6、IL-10或干扰素-γ孵育后进一步上调。此外，肿瘤相关巨噬细胞(TM Phi S)的上清液通过产生IL-6和IL-10上调B7-H4表面的表达。在NHL细胞中表达的B7-H4抑制NHL反应性T细胞的细胞毒活性。相反，抑制NHL细胞中的B7-H4可促进T细胞免疫，并使NHL细胞对细胞溶解致敏。此外，TM Phi S诱导的B7-H4促进了非霍奇金淋巴瘤细胞对T细胞免疫应答的逃避。综上所述，本研究表明NHL表达的B7-H4是一种重要的免疫抑制因子，可抑制宿主对NHL的抗肿瘤免疫。因此，靶向肿瘤表达的B7-H4可能为NHL患者提供一种新的治疗策略。
Non-Hodgkin lymphoma (NHL) is an incurable lymphoproliferative cancer, and patients with NHL have a poor prognosis. The present study explored the regulatory mechanism of expression and possible roles of the immunosuppressive B7-H4 molecule in human NHL. For functional studies, NHL-reactive T cell lines were generated via the isolation of allogeneic CD3(+) T cells from healthy donors and repeated in vitro stimulation with irradiated NHL cells isolated from patients. B7-H4 was found to be distributed in NHL cells and tissues, and its surface protein expression levels were further upregulated by the incubation of NHL cells with interleukin (IL)-6, IL-10, or interferon-gamma. Additionally, the supernatants of tumor-associated macrophages (tM phi s) upregulated B7-H4 surface expression by producing IL-6 and IL-10. B7-H4 expressed in NHL cells inhibited the cytotoxic activity of NHL-reactive T cells. Conversely, the inhibition of B7-H4 in NHL cells promoted T cell immunity and sensitized NHL cells to cytolysis. Furthermore, tM phi s induced B7-H4 promoted NHL cell evasion of the T cell immune response. In conclusion, this study shows that NHL-expressed B7-H4 is an important immunosuppressive factor that inhibits host anti-tumor immunity to NHL. Targeting tumor-expressed B7-H4 may thus provide a new treatment strategy for NHL patients.