Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Blockade of the Phagocytic Receptor MerTK on Tumor-Associated Macrophages Enhances P2X7R-Dependent STING Activation by Tumor-Derived cGAMP.
Immunity ( IF 25.5 ) Pub Date : 2020-02-11 , DOI: 10.1016/j.immuni.2020.01.014 Yi Zhou 1 , Mingjian Fei 1 , Gu Zhang 1 , Wei-Ching Liang 1 , WeiYu Lin 1 , Yan Wu 1 , Robert Piskol 1 , John Ridgway 1 , Erin McNamara 1 , Haochu Huang 1 , Juan Zhang 1 , Jaehak Oh 1 , Jaina M Patel 2 , Diana Jakubiak 1 , Jeff Lau 1 , Beth Blackwood 1 , Daniel D Bravo 1 , Yongchang Shi 1 , Jianyong Wang 1 , Hong-Ming Hu 2 , Wyne P Lee 1 , Rajiv Jesudason 1 , Dewakar Sangaraju 1 , Zora Modrusan 1 , Keith R Anderson 1 , Søren Warming 1 , Merone Roose-Girma 1 , Minhong Yan 1
Immunity ( IF 25.5 ) Pub Date : 2020-02-11 , DOI: 10.1016/j.immuni.2020.01.014 Yi Zhou 1 , Mingjian Fei 1 , Gu Zhang 1 , Wei-Ching Liang 1 , WeiYu Lin 1 , Yan Wu 1 , Robert Piskol 1 , John Ridgway 1 , Erin McNamara 1 , Haochu Huang 1 , Juan Zhang 1 , Jaehak Oh 1 , Jaina M Patel 2 , Diana Jakubiak 1 , Jeff Lau 1 , Beth Blackwood 1 , Daniel D Bravo 1 , Yongchang Shi 1 , Jianyong Wang 1 , Hong-Ming Hu 2 , Wyne P Lee 1 , Rajiv Jesudason 1 , Dewakar Sangaraju 1 , Zora Modrusan 1 , Keith R Anderson 1 , Søren Warming 1 , Merone Roose-Girma 1 , Minhong Yan 1
Affiliation
|
Clearance of apoptotic cells by macrophages prevents excessive inflammation and supports immune tolerance. Here, we examined the effect of blocking apoptotic cell clearance on anti-tumor immune response. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulation of apoptotic cells within tumors and triggered a type I interferon response. Treatment of tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergized with anti-PD-1 or anti-PD-L1 therapy. The anti-tumor effect induced by anti-MerTK treatment 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 P2X7R channel also compromised the effects of MerTK blockade. Mechanistically, extracellular ATP acted via P2X7R to enhance the transport of extracellular cGAMP into macrophages and subsequent STING activation. Thus, MerTK blockade increases tumor immunogenicity and potentiates anti-tumor immunity, which has implications for cancer immunotherapy.
中文翻译：
对肿瘤相关巨噬细胞的吞噬受体MerTK的阻断增强了肿瘤衍生cGAMP对P2X7R依赖性STING的活化作用。
巨噬细胞清除凋亡细胞可防止过度炎症并支持免疫耐受。在这里，我们检查了阻止凋亡细胞清除对抗肿瘤免疫反应的影响。我们产生了一种通过吞噬受体MerTK选择性抑制胞吞的抗体。MerTK的阻断导致肿瘤细胞内凋亡细胞的积累，并引发I型干扰素反应。用抗MerTK抗体治疗荷瘤小鼠可刺激T细胞活化，并与抗PD-1或抗PD-L1疗法协同作用。抗MerTK处理诱导的抗肿瘤作用在Stinggt / gt小鼠中消失，而在Cgas-/-小鼠中则没有。废除Cgas //-肿瘤细胞中的cGAMP产生，细胞外ATP耗竭或ATP门控的P2X7R通道失活也损害了MerTK阻断作用。从机制上讲，细胞外ATP通过P2X7R起作用，以增强细胞外cGAMP向巨噬细胞的转运以及随后的STING激活。因此，MerTK阻断增加了肿瘤的免疫原性并增强了抗肿瘤免疫力，这对癌症免疫治疗具有重要意义。
更新日期：2020-02-11
中文翻译：
对肿瘤相关巨噬细胞的吞噬受体MerTK的阻断增强了肿瘤衍生cGAMP对P2X7R依赖性STING的活化作用。
巨噬细胞清除凋亡细胞可防止过度炎症并支持免疫耐受。在这里，我们检查了阻止凋亡细胞清除对抗肿瘤免疫反应的影响。我们产生了一种通过吞噬受体MerTK选择性抑制胞吞的抗体。MerTK的阻断导致肿瘤细胞内凋亡细胞的积累，并引发I型干扰素反应。用抗MerTK抗体治疗荷瘤小鼠可刺激T细胞活化，并与抗PD-1或抗PD-L1疗法协同作用。抗MerTK处理诱导的抗肿瘤作用在Stinggt / gt小鼠中消失，而在Cgas-/-小鼠中则没有。废除Cgas //-肿瘤细胞中的cGAMP产生，细胞外ATP耗竭或ATP门控的P2X7R通道失活也损害了MerTK阻断作用。从机制上讲，细胞外ATP通过P2X7R起作用，以增强细胞外cGAMP向巨噬细胞的转运以及随后的STING激活。因此，MerTK阻断增加了肿瘤的免疫原性并增强了抗肿瘤免疫力，这对癌症免疫治疗具有重要意义。
京公网安备 11010802027423号