科學家繪製出癌細胞逃避T細胞殺傷的功能基因組圖譜
作者：
小柯機器人發布時間：2020/9/25 10:26:42
加拿大多倫多大學Jason Moffat團隊繪製出癌細胞逃避T細胞殺傷的功能基因組圖譜。這一研究成果於2020年9月23日在線發表在國際學術期刊《自然》上。
為了確定一個表型上強大的基因和通路核心集，從而使癌細胞能夠逃避細胞毒性T淋巴細胞（CTL）介導的殺傷作用，研究人員在一組與CTL共同培養的多種遺傳差異小鼠癌細胞系中進行了全基因組CRISPR篩選。研究人員在這些小鼠癌症模型中確定了182個基因的核心集，其單個幹擾增加了癌細胞對CTL介導的毒性敏感或抵抗。
使用遺傳共相似性對這一數據集進行系統的探索揭示出基因和途徑在癌細胞中起作用，從而協調其對CTL逃避的分級和協調方式，並顯示了控制幹擾素反應和腫瘤壞死因子（TNF）的離散功能模塊誘導的細胞毒性是主要的亞表型。這些數據為以前被鑑定為II型幹擾素應答的負調節劑的基因（例如Ptpn2、Socs1和Adar1）在介導CTL逃逸中建立了核心作用，並表明需要與脂質相關的基因Fitm2用於在暴露於幹擾素-γ（IFNγ）後保持細胞健康。
此外，研究人員確定自噬途徑是癌細胞逃避CTL的保守介導者，並表明該途徑需要抵抗細胞因子IFNγ和TNF誘導的細胞毒性。通過基於細胞因子和基於CTL的遺傳相互作用定位以及體內CRISPR篩選，研究人員展示了自噬的多效性效應如何控制CTL殺傷癌細胞，並且研究人員強調了這些效應在腫瘤內的重要性微環境。
總體而言，這些數據擴展了人們對癌細胞逃避免疫系統相關遺傳迴路的了解，並突出了有助於與CTL殺傷相關表型的遺傳相互作用。
據悉，使得癌細胞逃避宿主免疫系統破壞的遺傳迴路仍然知之甚少。
附：英文原文
Title: Functional genomic landscape of cancer-intrinsic evasion of killing by T cells
Author: Keith A. Lawson, Cristovo M. Sousa, Xiaoyu Zhang, Eiru Kim, Rummy Akthar, Joseph J. Caumanns, Yuxi Yao, Nicholas Mikolajewicz, Catherine Ross, Kevin R. Brown, Abdelrahman Abou Zid, Zi Peng Fan, Shirley Hui, Jordan A. Krall, Donald M. Simons, Chloe J. Slater, Victor De Jesus, Lujia Tang, Richa Singh, Joshua E. Goldford, Sarah Martin, Qian Huang, Elizabeth A. Francis, Andrea Habsid, Ryan Climie, David Tieu, Jiarun Wei, Ren Li, Amy Hin Yan Tong, Michael Aregger, Katherine S. Chan, Hong Han, Xiaowei Wang, Patricia Mero, John H. Brumell, Antonio Finelli, Laurie Ailles, Gary Bader, Gromoslaw A. Smolen, Gillian A. Kingsbury, Traver Hart, Charles Kung, Jason Moffat
Issue&Volume: 2020-09-23
Abstract: The genetic circuits that allow cancer cells to evade destruction by the host immune system remain poorly understood1,2,3. Here, to identify a phenotypically robust core set of genes and pathways that enable cancer cells to evade killing mediated by cytotoxic T lymphocytes (CTLs), we performed genome-wide CRISPR screens across a panel of genetically diverse mouse cancer cell lines that were cultured in the presence of CTLs. We identify a core set of 182 genes across these mouse cancer models, the individual perturbation of which increases either the sensitivity or the resistance of cancer cells to CTL-mediated toxicity. Systematic exploration of our dataset using genetic co-similarity reveals the hierarchical and coordinated manner in which genes and pathways act in cancer cells to orchestrate their evasion of CTLs, and shows that discrete functional modules that control the interferon response and tumour necrosis factor (TNF)-induced cytotoxicity are dominant sub-phenotypes. Our data establish a central role for genes that were previously identified as negative regulators of the type-II interferon response (for example, Ptpn2, Socs1 and Adar1) in mediating CTL evasion, and show that the lipid-droplet-related gene Fitm2 is required for maintaining cell fitness after exposure to interferon-γ (IFNγ). In addition, we identify the autophagy pathway as a conserved mediator of the evasion of CTLs by cancer cells, and show that this pathway is required to resist cytotoxicity induced by the cytokines IFNγ and TNF. Through the mapping of cytokine- and CTL-based genetic interactions, together with in vivo CRISPR screens, we show how the pleiotropic effects of autophagy control cancer-cell-intrinsic evasion of killing by CTLs and we highlight the importance of these effects within the tumour microenvironment. Collectively, these data expand our knowledge of the genetic circuits that are involved in the evasion of the immune system by cancer cells, and highlight genetic interactions that contribute to phenotypes associated with escape from killing by CTLs.
DOI: 10.1038/s41586-020-2746-2
Source: https://www.nature.com/articles/s41586-020-2746-2