阻断MerTK受体增强了抗肿瘤免疫
2020-02-13   阅读:573   来源:细胞

通过肿瘤衍生cGAMP阻断肿瘤相关巨噬细胞的MerTK吞噬受体增强了P2X7R依赖的STING激活,这一成果由美国基因泰克公司严民宏研究组取得。 这一研究成果于2020年2月11日在线发表在国际学术期刊《免疫》上。

研究人员探索了阻碍凋亡细胞的清除对抗肿瘤免疫反应的影响。研究人员制备了可通过吞噬受体MerTK选择性抑制胞吞作用的抗体。阻断MerTK导致肿瘤内凋亡细胞的积累,并引发I型干扰素反应。用抗MerTK抗体治疗荷瘤小鼠可激活T细胞活化,并与抗PD-1或抗PD-L1疗法协同作用。由抗MerTK处理引起的抗肿瘤作用在Stinggt / gt小鼠中消失,但在Cgas -/-小鼠中却没有。阻碍Cgas -/-肿瘤细胞中cGAMP的产生、消耗细胞外的ATP或ATP门控的P2X7R通道失活也损害了MerTK阻断的作用。从机制上讲,细胞外ATP通过P2X7R起作用,以增强细胞外cGAMP向巨噬细胞的转运随后激活STING。因此,MerTK阻断增加了肿瘤的免疫原性并增强了抗肿瘤免疫反应,这对癌症免疫治疗具有重要意义。

研究人员表示,巨噬细胞清除凋亡细胞可防止过度炎症并增强免疫耐受。

附:英文原文

Title: Blockade of the Phagocytic Receptor MerTK on Tumor-Associated Macrophages Enhances P2X7R-Dependent STING Activation by Tumor-Derived cGAMP

Author: Yi Zhou, Mingjian Fei, Gu Zhang, Wei-Ching Liang, WeiYu Lin, Yan Wu, Robert Piskol, John Ridgway, Erin McNamara, Haochu Huang, Juan Zhang, Jaehak Oh, Jaina M. Patel, Diana Jakubiak, Jeff Lau, Beth Blackwood, Daniel D. Bravo, Yongchang Shi, Jianyong Wang, Hong-Ming Hu, Wyne P. Lee, Rajiv Jesudason, Dewakar Sangaraju, Zora Modrusan, Keith R. Anderson, Sren Warming, Merone Roose-Girma, Minhong Yan

Issue&Volume: February 11, 2020

Abstract: Clearance of apoptotic cells by macrophages prevents excessive inflammation and supportsimmune tolerance. Here, we examined the effect of blocking apoptotic cell clearanceon anti-tumor immune response. We generated an antibody that selectively inhibitedefferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulationof apoptotic cells within tumors and triggered a type I interferon response. Treatmentof tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergizedwith anti-PD-1 or anti-PD-L1 therapy. The anti-tumor effect induced by anti-MerTKtreatment was lost in Stinggt/gt mice, but not in Cgas/ mice. Abolishing cGAMP production in Cgas/ tumor cells, depletion of extracellular ATP, or inactivation of the ATP-gated P2X7Rchannel also compromised the effects of MerTK blockade. Mechanistically, extracellularATP acted via P2X7R to enhance the transport of extracellular cGAMP into macrophagesand subsequent STING activation. Thus, MerTK blockade increases tumor immunogenicityand potentiates anti-tumor immunity, which has implications for cancer immunotherapy.

DOI: 10.1016/j.immuni.2020.01.014

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