Interdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy.
Interdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy.
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DOI：
10.1038/ncomms12335
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发表时间：
2016-08-08
影响因子：
16.6
通讯作者：
Sharma P
中科院分区：
文献类型：
--
作者：
Shi LZ;Fu T;Guan B;Chen J;Blando JM;Allison JP;Xiong L;Subudhi SK;Gao J;Sharma P
α-CTLA-4和α-PD-1联合治疗不同类型的肿瘤均有显著的临床疗效。然而，潜在的机制仍然难以捉摸。在这里，结合对人类肿瘤样本和临床前肿瘤模型的详细分析，我们报告了CTLA-4和PD-1的联合阻断可改善抗肿瘤免疫反应并协同根除肿瘤。从机制上讲，联合治疗依赖于T细胞中IL-7和IFN-γ信号之间的相互依赖，因为缺乏任何一种途径都会取消联合治疗的免疫增强和治疗效果。联合治疗以IFN-γ/IFN-γ r信号依赖的方式增加肿瘤浸润T细胞上IL-7Rα的表达，这可能作为免疫检查点阻断临床试验的潜在生物标志物。我们的数据表明，将免疫检查点阻断与IL-7信号联用可能是提高免疫治疗效果的有效方式。综上所述，我们得出结论，联合治疗通过IFN-γ/IFN-γ r和IL-7/IL-7R途径之间复杂的相互作用，有效地逆转免疫抑制并根除肿瘤。α-CTLA-4与α-PD-1联合治疗在临床试验中显示出较好的疗效。在这里，作者报道，在膀胱癌中，这种作用的机制取决于由IL-7/IL-7R和IFN-γ/IFN-γ r信号通路介导的T细胞活性上调。
Combination therapy with α-CTLA-4 and α-PD-1 has shown significant clinical responses in different types of cancer. However, the underlying mechanisms remain elusive. Here, combining detailed analysis of human tumour samples with preclinical tumour models, we report that concomitant blockade of CTLA-4 and PD-1 improves anti-tumour immune responses and synergistically eradicates tumour. Mechanistically, combination therapy relies on the interdependence between IL-7 and IFN-γ signalling in T cells, as lack of either pathway abrogates the immune-boosting and therapeutic effects of combination therapy. Combination treatment increases IL-7Rα expression on tumour-infiltrating T cells in an IFN-γ/IFN-γR signalling-dependent manner, which may serve as a potential biomarker for clinical trials with immune checkpoint blockade. Our data suggest that combining immune checkpoint blockade with IL-7 signalling could be an effective modality to improve immunotherapeutic efficacy. Taken together, we conclude that combination therapy potently reverses immunosuppression and eradicates tumours via an intricate interplay between IFN-γ/IFN-γR and IL-7/IL-7R pathways. Combination therapy with α-CTLA-4 and α-PD-1 is showing improved therapeutic effects in clinical trials. Here, the authors report that mechanistically in bladder cancer such effect depends upon an upregulation of T cell activity mediated by the IL-7/IL-7R and IFN-γ/IFN-γR signalling pathways.