小柯机器人

美国斯坦福大学医学院Michael C. Bassik小组通过细胞间CRISPR筛选揭示了调控癌细胞吞噬作用的调节因子。这一研究成果在线发表在2021年9月8日的国际学术期刊《自然》上。

在本研究中，研究人员研发了一个应用平台，可在癌细胞和巨噬细胞中使用互补的全基因组CRISPR敲除和过表达筛选，来无偏倚地识别阻碍抗体依赖性细胞吞噬作用(ADCP)的因子。在癌细胞中，除了CD47等已知因子外，研究人员还确定了许多对ADCP易感的调节因子，包括之前未知的酶脂肪细胞质膜相关蛋白 (APMAP)。研究发现APMAP缺失与肿瘤抗原靶向单克隆抗体和/或CD47阻断单克隆抗体协同作用，从而显著增加对多种类型癌细胞的吞噬作用，包括那些对ADCP具有抗性的细胞。

此外，研究还表明APMAP缺失与几种不同的肿瘤靶向单克隆抗体协同作用，从而抑制小鼠肿瘤的生长。在巨噬细胞中使用全基因组抗性筛选，研究人员发现G蛋白偶联受体GPR84增强了对APMAP缺陷癌细胞的吞噬作用。这项工作揭示了对抗体诱导吞噬作用易感癌症的内在调节因子，并广泛地扩展了人们对调控癌细胞逃避巨噬细胞吞噬作用机制的见解。 

据悉，靶向肿瘤抗原的单克隆抗体疗法在很大程度上通过引起巨噬细胞的吞噬作用来消除癌细胞。然而，癌细胞使用未知的机制来逃避吞噬作用。

附：英文原文

Title: Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis

Author: Kamber, Roarke A., Nishiga, Yoko, Morton, Bhek, Banuelos, Allison M., Barkal, Amira A., Vences-Cataln, Felipe, Gu, Mingxin, Fernandez, Daniel, Seoane, Jose A., Yao, David, Liu, Katherine, Lin, Sijie, Spees, Kaitlyn, Curtis, Christina, Jerby-Arnon, Livnat, Weissman, Irving L., Sage, Julien, Bassik, Michael C.

Issue&Volume: 2021-09-08

Abstract: Monoclonal antibody therapies targeting tumour antigens drive cancer cell elimination in large part by triggering macrophage phagocytosis of cancer cells1,2,3,4,5,6,7. However, cancer cells evade phagocytosis using mechanisms that are incompletely understood. Here we develop a platform for unbiased identification of factors that impede antibody-dependent cellular phagocytosis (ADCP) using complementary genome-wide CRISPR knockout and overexpression screens in both cancer cells and macrophages. In cancer cells, beyond known factors such as CD47, we identify many regulators of susceptibility to ADCP, including the poorly characterized enzyme adipocyte plasma membrane-associated protein (APMAP). We find that loss of APMAP synergizes with tumour antigen-targeting monoclonal antibodies and/or CD47-blocking monoclonal antibodies to drive markedly increased phagocytosis across a wide range of cancer cell types, including those that are otherwise resistant to ADCP. Additionally, we show that APMAP loss synergizes with several different tumour-targeting monoclonal antibodies to inhibit tumour growth in mice. Using genome-wide counterscreens in macrophages, we find that the G-protein-coupled receptor GPR84 mediates enhanced phagocytosis of APMAP-deficient cancer cells. This work reveals a cancer-intrinsic regulator of susceptibility to antibody-driven phagocytosis and, more broadly, expands our knowledge of the mechanisms governing cancer resistance to macrophage phagocytosis.

DOI: 10.1038/s41586-021-03879-4

Source: https://www.nature.com/articles/s41586-021-03879-4

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
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