Interferon-gamma-dependent infiltration of human T cells into neuroblastoma tumors in vivo.
Interferon-gamma-dependent infiltration of human T cells into neuroblastoma tumors in vivo.
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DOI：
10.1158/1078-0432.ccr-09-0829
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发表时间：
2009-11-01
期刊：
影响因子：
--
通讯作者：
Vonderheide RH
中科院分区：
文献类型：
--
作者：
Reid GS;Shan X;Coughlin CM;Lassoued W;Pawel BR;Wexler LH;Thiele CJ;Tsokos M;Pinkus JL;Pinkus GS;Grupp SA;Vonderheide RH
研究IFN-γ介导的MHC I类分子表达上调对体内肿瘤特异性T细胞毒性和T细胞向神经母细胞瘤肿瘤中运输的影响。通过IFN-γ处理恢复MHC I类表达增强了对神经母细胞瘤细胞的杀伤。为了了解这种方法在体内的潜力，我们开发了一种新的神经母细胞瘤模型，其中NOD/scid/IL 2 Rgammanull免疫缺陷小鼠移植有人类T细胞和肿瘤细胞。在这里，我们展示了体外患者来源的肿瘤特异性T细胞对神经母细胞瘤细胞的杀伤增强。此外，体内IFN-γ治疗诱导成神经细胞瘤肿瘤细胞上MHC I类表达的有效上调，并且这伴随着T细胞向肿瘤中的浸润的显著增强。在高危神经母细胞瘤患者的初步临床试验中，我们同样观察到全身IFN-γ治疗5天后患者肿瘤活检标本中T细胞向神经母细胞瘤巢的运输增加。IFN-γ克服了特异性T细胞杀死人神经母细胞瘤细胞的关键障碍。总之，这些发现为进一步测试IFN-γ作为改善神经母细胞瘤和其他MHC I类缺陷型恶性肿瘤的基于T细胞的疗法的疗效的方法提供了依据。此外，我们描述了一种模型，可以加快临床前筛选的方法，旨在增加T细胞贩运到人类肿瘤。
To investigate the impact of IFN-γ-mediated upregulation of MHC Class I expression on tumor-specific T cell cytotoxicity and T cell trafficking into neuroblastoma tumors in vivo. Restoration of MHC Class I expression by IFN-γ treatment enhances killing of neuroblastoma cells. To understand the potential of this approach in vivo, we developed a novel model of neuroblastoma in which NOD/scid/IL2Rgammanull immunodeficient mice are engrafted with both human T cells and tumor cells. Here we show enhanced killing of neuroblastoma cells by patient-derived, tumor-specific T cells in vitro. In addition, IFN-γ treatment in vivo induces efficient upregulation of MHC Class I expression on neuroblastoma tumor cells, and this is accompanied by significantly enhanced infiltration of T cells into the tumor. In a pilot clinical trial in patients with high-risk neuroblastoma, we similarly observed augmented T cell trafficking into neuroblastoma nests in tumor biopsy specimens obtained from patients after 5 days of systemic IFN-γ therapy. IFN-γ overcomes critical obstacles to the killing of human neuroblastoma cells by specific T cells. Together, these findings provide a rationale for the further testing of IFN-γ as an approach for improving the efficacy of T cell-based therapies for neuroblastoma and other MHC Class I-deficient malignancies. In addition, we describe a model that may expedite the pre-clinical screening of approaches aimed at augmenting T cell trafficking into human tumors.