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首页> 外文期刊>Progress in Artificial Intelligence >Isolated limb perfusion with melphalan activates interferon-stimulated genes to induce tumor regression in patients with melanoma in-transit metastasis
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Isolated limb perfusion with melphalan activates interferon-stimulated genes to induce tumor regression in patients with melanoma in-transit metastasis

机译：与Melphalan的分离的肢体灌注激活干扰素刺激的基因，以诱导患有黑色素瘤中的患者的肿瘤消退转移

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摘要

Hyperthermic isolated limb perfusion (ILP) with high-dose melphalan is a treatment option for melanoma patients with metastasis confined to limbs (in-transit metastasis). The therapy entails a complete response (CR) rate of 50-70%. Cellular immunity is proposed to impact on the clinical efficacy of ILP, but the detailed aspects of ILP-induced immune activation remain to be explored. For this study, we explored the potential role of interferon-stimulated gene (ISG) products, including CXCL10, CCL2, PD-L2 and IFN-gamma along with expression of their cognate receptors CXCR3, CCR4, CCR5 and PD-1 on lymphocytes, for the clinical efficacy of ILP. Patients with high serum levels of CXCL10, CCL2, PD-L2 and IFN-gamma were more likely to achieve CR after ILP. Additionally, the expression of CXCR3, CCR4 and CCR5 on T cells and/or natural killer (NK) cells was enhanced by ILP. Peripheral blood mononuclear cells (PBMCs) secreted high levels of CXCL10, CCL2 and IFN-gamma in response to co-culture with melphalan-exposed melanoma cells in vitro. Activated T cells migrated toward supernatants from these co-cultures. Furthermore, melphalan-exposed melanoma cells triggered upregulation of CXCR3, CCR4, CCR5 and PD-1 on co-cultured T cells and/or NK cells. Our results suggest that constituents released from melphalan-exposed melanoma cells stimulate the ISG axis with ensuing formation of chemokines and upregulation of chemokine receptor expression on anti-neoplastic immune cells, which may contribute in ILP-induced tumor regression.
机译：高温隔离肢体灌注（ILP）具有高剂量蛋白酶是黑色素瘤患者的治疗选项，该转移局限于四肢（在过渡转移）。该治疗需要完全响应（CR）率为50-70％。提出细胞免疫影响ILP的临床疗效，但仍有待探索ILP诱导的免疫激活的详细方面。对于本研究，我们探讨了干扰素刺激的基因（ISG）产品的潜在作用，包括CXCl10，CCL2，PD-L2和IFN-Gamma以及其同源受体CXCR3，CCR4，CCR5和PD-1在淋巴细胞上的表达，用于ILP的临床疗效。患有高血清CXCL10，CCL2，PD-L2和IFN-γ的患者更可能在ILP后实现Cr。另外，通过ILP提高了CXCR3，CCR4和CCR5对T细胞和/或天然杀伤（NK）细胞的表达。外周血单核细胞（PBMCs）分泌高水平的CXCL10，CCL2和IFN-GAMMA，响应于在体外与莫酚暴露的黑色素瘤细胞共培养。活化的T细胞从这些共培养物中迁移到上清液中。此外，莫酚暴露的黑色素瘤细胞在共培养的T细胞和/或NK细胞上引发了CXCR3，CCR4，CCR5和PD-1的上调。我们的研究结果表明，来自莫酚暴露的黑色素瘤细胞释放的成分刺激了ISG轴，随后形成趋化因子和趋化因子受体表达上调的抗肿瘤免疫细胞，这可能有助于ILP诱导的肿瘤回归。

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