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 名接受单独使用纳武单抗（抗 PD-1）或联合伊匹单抗（抗 CTLA-4）治疗的晚期黑色素瘤患者的基线和治疗中肿瘤活检的转录组。我们发现 T 细胞浸润和干扰素-γ (IFN-γ) 信号特征与临床治疗反应高度一致，响应活检中细胞周期和 WNT 信号通路的相互减少。我们模拟了 58 个人类细胞系中的相互作用，其中 IFN-γ体外除非细胞具有 IFN-γ 受体改变，否则暴露会导致保守的转录组反应。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 细胞反应的强度和相应的下游 IFN-γ 信号传导是临床反应或免疫检查点阻断疗法抵抗的主要驱动因素。