Ludwig Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland.
SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Cancer Res. 2017 Apr 1;77(7):1623-1636. doi: 10.1158/0008-5472.CAN-16-2680. Epub 2017 Jan 19.
Although mutations drive cancer, it is less clear to what extent genetic defects control immune mechanisms and confer resistance to T-cell-based immunotherapy. Here, we studied the reactions of malignant and benign melanocyte lines to cytotoxic CD8 T cells (CTL) using flow cytometry and gene expression analyses. We found rapid and broad upregulation of immune-regulatory genes, essentially triggered by CTL-derived IFNγ and augmented by TNFα. These reactions were predominantly homogenous, independent of oncogenic driver mutations, and similar in benign and malignant cells. The reactions exhibited both pro- and antitumorigenic potential and primarily corresponded to mechanisms that were conserved, rather than acquired, by mutations. Similar results were obtained from direct analysis of the tumor microenvironment. Thus, immune regulation in the tumor landscape may often be driven by conserved mechanisms, which may explain why T-cell-based immunotherapy can provide durable benefits with relatively infrequent escape. .
虽然突变驱动癌症，但遗传缺陷在多大程度上控制免疫机制并赋予对基于 T 细胞的免疫疗法的抗性尚不清楚。在这里，我们使用流式细胞术和基因表达分析研究了恶性和良性黑素细胞系对细胞毒性 CD8 T 细胞（CTL）的反应。我们发现免疫调节基因的快速广泛上调，主要由 CTL 衍生的 IFNγ触发，并被 TNFα增强。这些反应主要是同质的，与致癌驱动突变无关，在良性和恶性细胞中相似。这些反应表现出促肿瘤和抗肿瘤的潜力，主要对应于由突变保守而不是获得的机制。从肿瘤微环境的直接分析中也得到了类似的结果。因此，肿瘤景观中的免疫调节可能通常由保守机制驱动，这可以解释为什么基于 T 细胞的免疫疗法可以提供持久的益处，而逃逸相对较少。
