Effective anti-neu-initiated antitumor responses require the complex role of CD4+ T cells.
Effective anti-neu-initiated antitumor responses require the complex role of CD4+ T cells.
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DOI：
10.1158/1078-0432.ccr-12-2522
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发表时间：
2013-03-15
期刊：
影响因子：
--
通讯作者：
Fu YX
中科院分区：
文献类型：
--
作者：
Mortenson ED;Park S;Jiang Z;Wang S;Fu YX
用抗体靶向致癌受体被认为主要通过阻断致癌信号来抑制肿瘤生长。最近，获得性免疫，特别是CD 8 + T细胞的重要作用已被确定为抗HER 2/neu介导的肿瘤消退的主要因素。然而，CD 4 + T细胞的作用仍在定义中。本研究的目的是探讨CD 4 + T细胞是否以及在多大程度上参与介导抗HER 2/neu治疗的效果。使用大鼠HER 2/neu过表达细胞系TUBO的移植模型检查CD 4 + T细胞的作用。用抗neu疗法结合CD 4耗竭或CD 40 L阻断治疗荷瘤小鼠。通过肿瘤生长分析和ELISPOT检查CD 4耗竭对抗肿瘤应答的影响。除CD 8 + T细胞外，CD 4 + T细胞也是抗neu抗体介导的肿瘤消退所必需的，但不需要B细胞。CD 4+细胞的作用在整个抗neu治疗中是必要的，而不限于帮助CD 8 + T细胞。IFNγ的表达是抗neu治疗所必需的，并且IFNγ诱导TUBO细胞上的MHC-II表达，促进CD 4 + T细胞的直接识别。此外，肿瘤内消耗CD 4 + T细胞或阻断活化细胞表面蛋白CD 40 L抑制抗肿瘤反应。本研究揭示了CD 4 + T细胞在抗neu介导的肿瘤消退中的重要作用。
Targeting oncogenic receptors with antibodies has been thought to suppress tumor growth mainly by interrupting oncogenic signals. Recently, the essential role for adaptive immunity, and CD8+ T cells in particular, has been established as a major factor for anti-HER2/neu mediated tumor regression. However, the role of CD4+ T cells is still being defined. The purpose of this study was to explore whether and to what extent CD4+ T cells are involved in mediating the effects of anti-HER2/neu therapy. The role of CD4+ T cells was examined using a transplant model of the rat HER2/neu overexpressing cell line TUBO. Tumor bearing mice were treated with anti-neu therapy in conjunction with CD4 depletion or CD40L blockade. The effects of CD4 depletion on the anti-tumor response were examined by tumor growth analysis and ELISPOT. In addition to CD8+ T cells, CD4+ T cells are also essential for anti-neu antibody-mediated tumor regression, but B cells are not required. The role for CD4+ cells is necessary throughout anti-neu therapy and not limited to helping CD8+ T cells. Expression of IFNγ is necessary for anti-neu therapy and IFNγ induces MHC-II expression on TUBO cells promoting direct recognition by CD4+ T cells. Furthermore, intratumoral depletion of CD4+ T cells or blockade of the activating cell-surface protein CD40L inhibits the anti-tumor response. This study reveals essential role of CD4+ T cell for anti-neu mediated tumor regression.