小柯机器人

加拿大多伦多大学Jason Moffat团队绘制出癌细胞逃避T细胞杀伤的功能基因组图谱。这一研究成果于2020年9月23日在线发表在国际学术期刊《自然》上。

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

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/
投稿链接：http://www.nature.com/authors/submit_manuscript.html