当前位置: X-MOL 学术EMBO Rep. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
HOIP limits anti-tumor immunity by protecting against combined TNF and IFN-gamma-induced apoptosis
EMBO Reports ( IF 6.5 ) Pub Date : 2021-09-01 , DOI: 10.15252/embr.202153391
Andrew J Freeman 1, 2 , Stephin J Vervoort 2, 3 , Jessica Michie 1, 2 , Kelly M Ramsbottom 1 , John Silke 4, 5 , Conor J Kearney 2, 3 , Jane Oliaro 1, 2, 6
Affiliation  

The success of cancer immunotherapy is limited to a subset of patients, highlighting the need to identify the processes by which tumors evade immunity. Using CRISPR/Cas9 screening, we reveal that melanoma cells lacking HOIP, the catalytic subunit of LUBAC, are highly susceptible to both NK and CD8+ T-cell-mediated killing. We demonstrate that HOIP-deficient tumor cells exhibit increased sensitivity to the combined effect of the inflammatory cytokines, TNF and IFN-γ, released by NK and CD8+ T cells upon target recognition. Both genetic deletion and pharmacological inhibition of HOIP augment tumor cell sensitivity to combined TNF and IFN-γ. Together, we unveil a protective regulatory axis, involving HOIP, which limits a transcription-dependent form of cell death that engages both intrinsic and extrinsic apoptotic machinery upon exposure to TNF and IFN-γ. Our findings highlight HOIP inhibition as a potential strategy to harness and enhance the killing capacity of TNF and IFN-γ during immunotherapy.

中文翻译:

HOIP 通过防止 TNF 和 IFN-γ 联合诱导的细胞凋亡来限制抗肿瘤免疫

癌症免疫疗法的成功仅限于一部分患者,这凸显了确定肿瘤逃避免疫过程的必要性。使用 CRISPR/Cas9 筛选,我们发现缺乏 HOIP(LUBAC 的催化亚基)的黑色素瘤细胞对 NK 和 CD8 + T 细胞介导的杀伤高度敏感。我们证明 HOIP 缺陷型肿瘤细胞对由 NK 和 CD8 +释放的炎性细胞因子 TNF 和 IFN-γ 的联合作用表现出更高的敏感性目标识别后的 T 细胞。HOIP 的基因缺失和药理学抑制都增加了肿瘤细胞对联合 TNF 和 IFN-γ 的敏感性。总之,我们揭示了一个保护性调节轴,包括 HOIP,它限制了一种转录依赖性的细胞死亡形式,这种形式在暴露于 TNF 和 IFN-γ 时会同时参与内在和外在的凋亡机制。我们的研究结果强调了 HOIP 抑制是一种在免疫治疗期间利用和增强 TNF 和 IFN-γ 杀伤能力的潜在策略。
更新日期:2021-11-04
down
wechat
bug