干扰素-γ 信号通路的保守性驱动黑色素瘤对免疫检查点阻断治疗的临床应答。
Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma.
机构信息
Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
出版信息
Cancer Cell. 2020 Oct 12;38(4):500-515.e3. doi: 10.1016/j.ccell.2020.08.005. Epub 2020 Sep 10.
We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.
我们分析了 101 例接受单独纳武单抗（抗 PD-1）或联合伊匹单抗（抗 CTLA-4）治疗的晚期黑色素瘤患者基线期和治疗期肿瘤活检的转录组。我们发现 T 细胞浸润和干扰素-γ（IFN-γ）信号特征与治疗的临床反应最相关，在有应答的活检中细胞周期和 WNT 信号通路呈相反下降。我们在 58 个人类细胞系中进行了模型构建，其中 IFN-γ 在体外暴露会导致保守的转录组反应，除非细胞有 IFN-γ 受体改变。黑色素瘤细胞中这种保守的 IFN-γ 转录组反应有助于放大抗肿瘤免疫反应。因此，抗肿瘤 T 细胞反应的程度和相应的下游 IFN-γ 信号是临床反应或对免疫检查点阻断治疗耐药的主要驱动因素。
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