RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer.
RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer.
复制标题
RIP1激酶驱动胰腺癌中巨噬细胞介导的适应性免疫耐受。
DOI：
10.1016/j.ccell.2018.10.006
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发表时间：
2018-11-12
期刊：
影响因子：
50.3
通讯作者：
Miller G
中科院分区：
文献类型：
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作者：
Wang W;Marinis JM;Beal AM;Savadkar S;Wu Y;Khan M;Taunk PS;Wu N;Su W;Wu J;Ahsan A;Kurz E;Chen T;Yaboh I;Li F;Gutierrez J;Diskin B;Hundeyin M;Reilly M;Lich JD;Harris PA;Mahajan MK;Thorpe JH;Nassau P;Mosley JE;Leinwand J;Kochen Rossi JA;Mishra A;Aykut B;Glacken M;Ochi A;Verma N;Kim JI;Vasudevaraja V;Adeegbe D;Almonte C;Bagdatlioglu E;Cohen DJ;Wong KK;Bertin J;Miller G
胰腺导管腺癌(PDA)具有免疫耐受和免疫治疗抵抗的特点。我们发现PDA患者肿瘤相关巨噬细胞(TAM)中受体相互作用的丝氨酸/苏氨酸蛋白激酶1(RIP1)表达上调。为了研究它在肿瘤进展中的作用，我们开发了一种选择性的小分子RIP1抑制剂，在体内暴露很高。靶向RIP1以STAT1依赖的方式将TAM重新编程为MHCIIhi肿瘤坏死因子α+干扰素γ+免疫原型。抑制TAMS中的RIP1导致细胞毒性T细胞激活和T辅助细胞向混合Th1/Th17表型分化，从而在小鼠和人PDA器官模型中产生肿瘤免疫。靶向RIP1与基于PD1和ICOS的免疫疗法协同作用。RIP1的促肿瘤作用与其与RIP3的协同作用无关。总而言之，我们的工作将RIP1描述为控制肿瘤免疫的检查点激酶。Wang等人。合成一种可在体内使用的选择性RIP1抑制剂。抑制RIP1在胰腺癌肿瘤相关巨噬细胞中的高表达，逆转局部免疫抑制，增强基于检查点和共刺激受体的免疫治疗的有效性。
Pancreatic ductal adenocarcinoma (PDA) is characterized by immune-tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine-protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T-helper cell differentiation towards a mixed Th1/Th17 phenotype, leading to tumor-immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1- and ICOS-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor-immunity. Wang et al. synthesize a selective RIP1 inhibitor that can be used in vivo. Inhibition of RIP1, which is highly expressed in tumor-associated macrophages in pancreatic ductal adenocarcinoma, reverses local immune-suppression and enhances the efficacy of checkpoint and costimulatory receptor-based immunotherapy.