Targeting TBK1 to overcome resistance to cancer immunotherapy.
Targeting TBK1 to overcome resistance to cancer immunotherapy.
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靶向TBK1克服对癌症免疫治疗的耐药性。
DOI：
10.1038/s41586-023-05704-6
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发表时间：
2023-03
期刊：
影响因子：
64.8
通讯作者：
Jenkins, Russell W. W.
中科院分区：
文献类型：
--
作者：
Sun, Yi;Revach, Or-yam;Anderson, Seth;Kessler, Emily A. A.;Wolfe, Clara H. H.;Jenney, Anne;Mills, Caitlin E. E.;Robitschek, Emily J. J.;Davis, Thomas G. R.;Kim, Sarah;Fu, Amina;Ma, Xiang;Gwee, Jia;Tiwari, Payal;Du, Peter P. P.;Sindurakar, Princy;Tian, Jun;Mehta, Arnav;Schneider, Alexis M. M.;Yizhak, Keren;Sade-Feldman, Moshe;LaSalle, Thomas;Sharova, Tatyana;Xie, Hongyan;Liu, Shuming;Michaud, William A. A.;Saad-Beretta, Rodrigo;Yates, Kathleen B. B.;Iracheta-Vellve, Arvin;Spetz, Johan K. E.;Qin, Xingping;Sarosiek, Kristopher A. A.;Zhang, Gao;Kim, Jong Wook;Su, Mack Y. Y.;Cicerchia, Angelina M. M.;Rasmussen, Martin Q. Q.;Klempner, Samuel J. J.;Juric, Dejan;Pai, Sara I. I.;Miller, David M. M.;Giobbie-Hurder, Anita;Chen, Jonathan H. H.;Pelka, Karin;Frederick, Dennie T. T.;Stinson, Susanna;Ivanova, Elena;Aref, Amir R. R.;Paweletz, Cloud P. P.;Barbie, David A. A.;Sen, Debattama R. R.;Fisher, David E. E.;Corcoran, Ryan B. B.;Hacohen, Nir;Sorger, Peter K. K.;Flaherty, Keith T. T.;Boland, Genevieve M. M.;Manguso, Robert T. T.;Jenkins, Russell W. W.
尽管 PD-1 阻断在黑色素瘤和其他癌症中取得了成功，但仍缺乏克服癌症免疫疗法耐药性的有效治疗策略。我们在汇总遗传筛选中将先天免疫激酶 TANK 结合激酶 1 (TBK1) 确定为候选免疫逃避基因。使用跨多个实验模型系统的一套遗传和药理学工具，我们确认了 TBK1 作为免疫逃避基因的作用。靶向 TBK1 通过降低效应细胞因子 (TNFα/IFNγ) 的细胞毒性阈值来增强对 PD-1 阻断的反应。 TBK1 抑制与 PD-1 阻断联合使用患者来源的肿瘤模型也证明了疗效，在匹配的患者来源的器官型肿瘤球体 (PDOTS) 和匹配的患者来源的类器官 (PDO) 中得到了一致的结果。缺乏 TBK1 的肿瘤细胞会以 JAK/STAT 依赖性方式响应 TNFα/IFNγ，从而经历 RIPK 和 caspase 依赖性细胞死亡。综上所述，我们的结果表明，靶向 TBK1 是克服癌症免疫治疗耐药性的一种新颖且有效的策略。
Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking. We identified the innate immune kinase TANK-binding kinase 1 (TBK1) as a candidate immune evasion gene in a pooled genetic screen. Using a suite of genetic and pharmacologic tools across multiple experimental model systems, we confirm a role for TBK1 as an immune evasion gene. Targeting TBK1 enhances response to PD-1 blockade by lowering the cytotoxicity threshold to effector cytokines (TNFα/IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids (PDOTS) and matched patient-derived organoids (PDOs). Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNFα/IFNγ in a JAK/STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy.
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影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
64.5
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
通讯作者：
Minn AJ
影响因子：
8.8
作者：
Jenkins RW;Barbie DA;Flaherty KT
通讯作者：
Flaherty KT
影响因子：
64.8
作者：
Ishizuka, Jeffrey J.;Manguso, Robert T.;Haining, W. Nicholas
通讯作者：
Haining, W. Nicholas
DOI：
10.1007/978-1-4939-8861-7_4
发表时间：
2019-01-01
期刊：
BCL-2 FAMILY PROTEINS
影响因子：
--
作者：
Fraser, Cameron;Ryan, Jeremy;Sarosiek, Kristopher
通讯作者：
Sarosiek, Kristopher