小柯机器人

美国哈佛医学院Russell W. Jenkins研究组发现，靶向TBK1可克服对癌症免疫疗法的耐药。2023年1月12日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员将固有免疫激酶TANK结合激酶1（TBK1）鉴定为汇合遗传筛选中的候选免疫逃避基因。通过使用多个实验模型系统中的一套遗传和药理学工具，研究人员证实了TBK1作为免疫逃避基因的作用。靶向TBK1通过降低对效应细胞因子（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阻断结合使用患者衍生的肿瘤模型也证明了功效，在匹配的患者衍生器官型肿瘤球体（PDOTS）和匹配的患者衍生类器官（PDOS）中具有一致的发现。缺乏TBK1的肿瘤细胞以JAK/STAT依赖性方式对TNFα/IFNγ响应响应TNFα/IFNγ进行RIPK和caspase依赖性细胞死亡。因此，这些结果表明，靶向TBK1是克服对癌症免疫疗法耐药的新型有效策略。

据介绍，尽管PD-1在黑色素瘤和其他癌症中取得了成功，但仍缺乏克服抗癌免疫疗法的有效治疗策略。

附：英文原文

Title: Targeting TBK1 to overcome resistance to cancer immunotherapy

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

Issue&Volume: 2023-01-12

Abstract: Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking1,2. We identified the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune evasion gene in a pooled genetic screen4. 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.

DOI: 10.1038/s41586-023-05704-6

Source: https://www.nature.com/articles/s41586-023-05704-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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