Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade.
Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade.
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DOI：
10.1016/j.cell.2016.11.022
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发表时间：
2016-12-01
期刊：
影响因子：
64.5
通讯作者：
Minn AJ
中科院分区：
文献类型：
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作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
PD1通路的治疗性阻断导致显著的肿瘤反应，但耐药性很常见。我们证明了延长的干扰素信号传导协调了对免疫检查点阻断（ICB）的PDL 1依赖性和PDL 1非依赖性抗性，以及对辐射加抗CTLA 4等组合的抗性。持续的II型干扰素信号传导允许肿瘤获得STAT1相关的表观基因组变化，并增强干扰素刺激的基因和多种T细胞抑制性受体的配体的表达。I型和II型干扰素都维持这种抵抗程序。在基因上削弱该程序或使其无效会干扰多种抑制途径，并扩大不同的T细胞群，尽管表达严重衰竭的标志物，但功能得到改善。因此，对多药剂ICB具有抗性的肿瘤对ICB单一疗法产生响应。最后，我们观察到干扰素驱动耐药的生物标志物与抗PD1治疗后的临床进展相关。因此，肿瘤干扰素信号传导的持续时间增加了适应性抗性，并且干扰素应答的抑制绕过了对组合ICB疗法的要求。肿瘤细胞中延长的干扰素信号传导增加了对免疫检查点阻断的抵抗力，抑制这种反应可以绕过这些药物与其他疗法联合使用的需要。
Therapeutic blocking of the PD1 pathway results in significant tumor responses but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB), and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways, and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies. Prolonged interferon signaling in tumor cells increases resistance to immune checkpoint blockade, and inhibiting this response can bypass the need for combination of these agents with other therapies.