以TBK1为靶点克服对癌症免疫治疗的耐药性

2023-02-09 09:32

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的有效策略。

SCI 8 February 2023

Targeting TBK1 to overcome resistance to cancer immunotherapy

(Nature, IF: 69.504)

Yi Sun, Or-yam Revach, Seth Anderson, Emily A. Kessler, Clara H. Wolfe, Anne Jenney, Caitlin E. Mills, Emily J. Robitschek, Thomas G. R. Davis, Sarah Kim, Amina Fu, Xiang Ma, Jia Gwee, Payal Tiwari, Peter P. Du, Princy Sindurakar, Jun Tian, Arnav Mehta, Alexis M. Schneider, Keren Yizhak, Moshe Sade-Feldman, Thomas LaSalle, Tatyana Sharova, Hongyan Xie, Shuming Liu, William A. Michaud, Rodrigo Saad-Beretta, Kathleen B. Yates, Arvin Iracheta-Vellve, Johan K. E. Spetz, Xingping Qin, Kristopher A. Sarosiek, Gao Zhang, Jong Wook Kim, Mack Y. Su, Angelina M. Cicerchia, Martin Q. Rasmussen, Samuel J. Klempner, Dejan Juric, Sara I. Pai, David M. Miller, Anita Giobbie-Hurder, Jonathan H. Chen, Karin Pelka, Dennie T. Frederick, Susanna Stinson, Elena Ivanova, Amir R. Aref, Cloud P. Paweletz, David A. Barbie, Debattama R. Sen, David E. Fisher, Ryan B. Corcoran, Nir Hacohen, Peter K. Sorger, Keith T. Flaherty, Genevieve M. Boland, Robert T. Manguso & Russell W. Jenkins

CORRESPONDENCE TO: rjenkins@mgh.harvard.edu

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.

尽管PD-1阻断剂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治疗耐药性的有效治疗策略。我们在汇集文库遗传筛选中确定了先天免疫激酶TANK结合激酶1（TBK1）作为候选免疫逃避基因。通过在多个实验模型系统中使用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。通过患者来源的肿瘤模型也证明了TBK1抑制与PD-1阻断联合使用的有效性，与匹配的患者来源的器官型肿瘤球体（PDOTS）和匹配的患者源的类器官（PDOs）中发现一致。缺乏TBK1的肿瘤细胞以JAK/STAT依赖的方式对TNFα/IFNγ作出反应，从而引发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的有效策略。