Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade.
Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade.
复制标题
治疗性地增加MHC-I表达增强免疫检查点封锁。
DOI：
10.1158/2159-8290.cd-20-0812
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发表时间：
2021-06
期刊：
影响因子：
28.2
通讯作者：
Liu XS
中科院分区：
文献类型：
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作者：
Gu SS;Zhang W;Wang X;Jiang P;Traugh N;Li Z;Meyer C;Stewig B;Xie Y;Bu X;Manos MP;Font-Tello A;Gjini E;Lako A;Lim K;Conway J;Tewari AK;Zeng Z;Sahu AD;Tokheim C;Weirather JL;Fu J;Zhang Y;Kroger B;Liang JH;Cejas P;Freeman GJ;Rodig S;Long HW;Gewurz BE;Hodi FS;Brown M;Liu XS
免疫检查点阻断（ICB）疗法彻底改变了癌症治疗，但许多MHC-I表达受损的患者仍然难治。在这里，我们将基于FACS的全基因组CRISPR筛选与数据挖掘方法相结合，以确定可以上调MHC-I而不诱导PD-L1的药物。CRISPR筛选鉴定了TRAF 3，一种NF-κB通路的抑制剂，作为MHC-I而不是PD-L1的负调节剂。Traf 3敲除（Traf 3-KO）基因表达特征与ICB初治癌症患者的更好生存率和更好的ICB反应相关。然后，我们筛选了具有类似转录效应的药物，并确定了SMAC模拟物。我们实验验证了SMAC模拟物birinapant上调MHC-I，使癌细胞对T细胞依赖性杀伤敏感，并增加ICB功效。我们的研究结果为用SMAC模拟物治疗表达低MHC-I表达的肿瘤以增强对免疫疗法的敏感性提供了临床前理论基础。本研究中使用的方法可以推广到识别其他增强免疫治疗效果的药物。
Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NF-κB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified SMAC mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T-cell-dependent killing, and adds to ICB efficacy. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy.