JAK inhibition selectively suppresses melanoma lacking IFN-? pathway

Immune checkpoint blockers (ICBs) showed unprecedented clinical benefits. But the overall efficacy of ICBs is limited to a small subset of cancer patients due to therapeutic resistance. Concerted efforts from our group and others have identified that loss of IFN-g signaling genes in melanoma is a major mechanism of resistance to ICBs. We therefore generated B16 melanoma model with IFNgR1 knocked out by CRISPR-Cas9. We sequenced the whole transcriptomes and identified activated PI3K-Akt-mTOR pathway in IFNgR1 knocked out cells. This may represent an attractive target for therapeutic interventions to bypassing ICB resistance in melanoma lacking functional IFN-g signaling. Overall design: Scramble and IFN?R1KO B16 melanoma cells were sent for transcriptomic analysis by paired-end RNAseq analysis to find the activation of PI3K-Akt-mTOR pathway in IFN?R1 knocked out cells.

免疫检查点阻断剂（immune checkpoint blockers, ICBs）展现出前所未有的临床治疗获益。但受限于治疗抗性，免疫检查点阻断剂的整体疗效仅能惠及少数癌症患者。本课题组与其他研究团队的协同研究证实，黑色素瘤中干扰素γ（interferon-gamma, IFN-γ）信号通路基因的缺失是引发免疫检查点阻断剂抗性的主要机制之一。为此，我们借助CRISPR-Cas9技术构建了IFNgR1基因敲除的B16黑色素瘤模型。我们对两组细胞的全转录组进行测序，发现IFNgR1敲除细胞中存在PI3K-Akt-mTOR通路（phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin pathway）的激活。该通路或可作为针对缺失功能性IFN-γ信号通路的黑色素瘤患者，规避免疫检查点阻断剂抗性的理想治疗靶点。整体实验设计：将阴性对照（Scramble）与IFNgR1敲除的B16黑色素瘤细胞进行双端RNA测序（paired-end RNAseq）转录组分析，以验证IFNgR1敲除细胞中PI3K-Akt-mTOR通路的激活状态。