ABSTRACT

Evaluation of: Gao J, Shi LZ, Zhao H et al. Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167(2), 397–404 (2016).

Tumor resistance to immune checkpoint inhibitors limits therapeutic efficacy in many cancer patients. The study by Gao et al. highlighted herein describes a fundamental mechanism by which melanoma escapes the CTLA-4-targeting drug ipilimumab, the first FDA-approved immune checkpoint inhibitor for cancer. This work describes genomic alterations to IFNγ signaling pathway components as a mechanism of melanoma resistance to ipilimumab and has spawned several studies documenting the significance of this pathway to the efficacy of immunotherapy. The authors highlight new analysis of TCGA RNA-seq data that both support and extend the relevance of the IFNγ pathway to CTLA-4 checkpoint blockade as first introduced by this seminal paper, and the authors discuss the relevance of these collective findings to the future of cancer immunotherapy.

摘要

评价：高洁，石立志，赵辉等。肿瘤细胞中IFN-γ通路基因的丧失是抗CTLA-4治疗耐药的机制。细胞167（2），397-404（2016）。

肿瘤对免疫检查点抑制剂的耐药性限制了许多癌症患者的治疗效果。高等人的研究。本文重点介绍了一种黑色素瘤逃脱CTLA-4靶向药物ipilimumab（一种首个FDA批准的癌症免疫检查点抑制剂）的基本机制。这项工作描述了对IFNγ信号通路成分的基因组改变，作为黑色素瘤对ipilimumab耐药的机制，并催生了数项研究，证实了该通路对免疫疗法功效的重要性。作者重点介绍了TCGA RNA-seq数据的新分析，该数据既支持并扩展了IFNγ途径与CTLA-4检查点封锁的相关性，又如该开创性论文首次介绍的那样，作者讨论了这些集体调查结果与未来FDA相关性。癌症免疫疗法。