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研究确定癌症免疫逃逸的机制
2021-03-02 15:25

美国哥伦比亚大学Benjamin Izar和麻省理工学院Aviv Regev研究组合作在研究中取得进展。他们利用患者模型中的多模式混合Perturb-CITE-seq筛查确定了癌症免疫逃逸的机制。该项研究成果发表在2021年3月1日出版的《自然-遗传学》杂志上。

为了阐明检查点抑制剂(ICIs)的耐药性潜在的机制,他们开发了Perturb-CITE测序(Perturb-CITE-seq),从而可以通过单细胞转录组和蛋白读数合并聚集的规则间隔的短回文重复序列(CRISPR)-Cas9扰动。在患者来源的黑色素瘤细胞和自体肿瘤浸润淋巴细胞(TIL)的共培养物中,他们在约750扰动与癌细胞内源性ICI抗性(ICR)相关的218,000细胞中分析了转录组和20种蛋白。他们恢复了已知的耐药机制,包括干扰素-γ(IFN-γ)–JAK / STAT的缺陷以及RNA、蛋白质和微扰空间中的抗原呈递途径,以及新的机制,包括CD58的丢失/下调。

CD58的丧失在多种共培养模型中均导致免疫逃逸,并在ICR黑色素瘤患者的肿瘤中被下调。CD58蛋白的表达不受IFN-γ信号的诱导,并且CD58的丧失在不损害主要组织相容性复合物(MHC)表达的情况下提供了免疫逃逸,表明它与ICR的已知机制正交。这项工作通过具有多模式单细胞读数的大规模干扰筛查为破译复杂机制提供了框架,并发现了潜在的临床上与免疫逃逸有关的机制。

附:英文原文

Title: Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion

Author: Chris J. Frangieh, Johannes C. Melms, Pratiksha I. Thakore, Kathryn R. Geiger-Schuller, Patricia Ho, Adrienne M. Luoma, Brian Cleary, Livnat Jerby-Arnon, Shruti Malu, Michael S. Cuoco, Maryann Zhao, Casey R. Ager, Meri Rogava, Lila Hovey, Asaf Rotem, Chantale Bernatchez, Kai W. Wucherpfennig, Bruce E. Johnson, Orit Rozenblatt-Rosen, Dirk Schadendorf, Aviv Regev, Benjamin Izar

Issue&Volume: 2021-03-01

Abstract: Resistance to immune checkpoint inhibitors (ICIs) is a key challenge in cancer therapy. To elucidate underlying mechanisms, we developed Perturb-CITE-sequencing (Perturb-CITE-seq), enabling pooled clustered regularly interspaced short palindromic repeat (CRISPR)–Cas9 perturbations with single-cell transcriptome and protein readouts. In patient-derived melanoma cells and autologous tumor-infiltrating lymphocyte (TIL) co-cultures, we profiled transcriptomes and 20proteins in ~218,000cells under ~750perturbations associated with cancer cell-intrinsic ICI resistance (ICR). We recover known mechanisms of resistance, including defects in the interferon-γ (IFN-γ)–JAK/STAT and antigen-presentation pathways in RNA, protein and perturbation space, and new ones, including loss/downregulation of CD58. Loss of CD58 conferred immune evasion in multiple co-culture models and was downregulated in tumors of melanoma patients with ICR. CD58 protein expression was not induced by IFN-γ signaling, and CD58 loss conferred immune evasion without compromising major histocompatibility complex (MHC) expression, suggesting that it acts orthogonally to known mechanisms of ICR. This work provides a framework for the deciphering of complex mechanisms by large-scale perturbation screens with multimodal, single-cell readouts, and discovers potentially clinically relevant mechanisms of immune evasion.

DOI: 10.1038/s41588-021-00779-1

Source: https://www.nature.com/articles/s41588-021-00779-1

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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