芬兰赫尔辛基大学Satu Mustjok等研究人员合作发现，单细胞功能基因组学揭示血癌中自然杀伤细胞敏感性和抵抗性的决定因素。该研究于2023年12月12日发表于国际一流学术期刊《免疫》杂志上。

为了揭示NK细胞活性易感性的遗传决定因素，研究人员利用单细胞和基因组规模的功能基因组学筛选研究了相互作用的自然杀伤（NK）细胞和血癌细胞。根据癌细胞系谱和分子表型的不同，NK细胞和癌细胞的相互作用在两种细胞类型中诱导了不同的激活和I型干扰素（IFN）状态，从敏感性较高的骨髓癌到敏感性较低的B淋巴癌不等。

在癌细胞中进行的CRISPR筛选发现了调节对NK细胞介导的杀伤敏感性和抵抗力的基因，包括粘附相关糖蛋白、蛋白岩藻糖基化基因和转录调节因子，此外还证实了抗原呈递和死亡受体信号通路的重要性。

研究人员利用单细胞转录组读出的CRISPR筛选深入了解了潜在的机制，包括癌细胞中IFN-γ信号的调控和NK细胞的激活状态。这些研究结果突显了不同癌症中影响NK细胞易感性的机制的多样性，并为基于NK细胞的疗法提供了资源。

据介绍，癌细胞可以逃避NK细胞的活性，从而限制抗肿瘤免疫。

附：英文原文

Title: Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers

Author: Olli Dufva, Sara Gandolfi, Jani Huuhtanen, Olga Dashevsky, Hanna Duàn, Khalid Saeed, Jay Klievink, Petra Nygren, Jonas Bouhlal, Jenni Lahtela, Anna Ntnen, Bishwa R. Ghimire, Tiina Hannunen, Pekka Ellonen, Hanna Lhteenmki, Pauliina Rumm, Jason Theodoropoulos, Essi Laajala, Jouni Hrknen, Petri Plnen, Merja Heinniemi, Maija Hollmén, Shizuka Yamano, Ryosuke Shirasaki, David A. Barbie, Jennifer A. Roth, Rizwan Romee, Michal Sheffer, Harri Lhdesmki, Dean A. Lee, Ricardo De Matos Simoes, Matti Kankainen, Constantine S. Mitsiades, Satu Mustjoki

Issue&Volume: 2023/12/12

Abstract: Cancer cells can evade natural killer (NK) cell activity, thereby limiting anti-tumor immunity. To reveal genetic determinants of susceptibility to NK cell activity, we examined interacting NK cells and blood cancer cells using single-cell and genome-scale functional genomics screens. Interaction of NK and cancer cells induced distinct activation and type I interferon (IFN) states in both cell types depending on the cancer cell lineage and molecular phenotype, ranging from more sensitive myeloid to less sensitive B-lymphoid cancers. CRISPR screens in cancer cells uncovered genes regulating sensitivity and resistance to NK cell-mediated killing, including adhesion-related glycoproteins, protein fucosylation genes, and transcriptional regulators, in addition to confirming the importance of antigen presentation and death receptor signaling pathways. CRISPR screens with a single-cell transcriptomic readout provided insight into underlying mechanisms, including regulation of IFN-γ signaling in cancer cells and NK cell activation states. Our findings highlight the diversity of mechanisms influencing NK cell susceptibility across different cancers and provide a resource for NK cell-based therapies.

DOI: 10.1016/j.immuni.2023.11.008

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00490-9