摘要:肿瘤细胞内禀BPTF抑制NK细胞活性和天然细胞毒性受体共配体的丰度

Kimberly Mayes, Zeinab Elsayed, Aiman S Alhazmi, M. Waters, Suehyb G. Alkhatib, Mark Roberts, Carolyn Song, Kristen Peterson, Vivian Chan, Nikhil Ailaney, Pumoli Malapati, T. Blevins, Berislav Lisnić, C. Dumur, Joseph W. Landry
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引用次数: 0

摘要

利用同基因BALB/c小鼠乳腺癌模型,我们发现染色质重塑亚基bromodomain PHD手指转录因子(BPTF)在肿瘤微环境(TME)中抑制自然杀伤细胞(NK)抗肿瘤活性。在培养中,BPTF抑制直接天然细胞毒性受体(NCR)介导的NK细胞对小鼠和人类癌细胞的细胞溶解活性,显示出保守的功能。在体内阻断小鼠NCR1可挽救BPTF KD肿瘤重量,证明其对控制肿瘤生长的重要性。我们发现BPTF占据肝素酶(Hpse)调控元件,激活其表达。肝素酶活性的增加导致NCR共配体:硫酸肝素蛋白聚糖(HSPGs)的细胞表面丰度降低。使用增益和功能损失的方法,我们表明升高的肝素酶水平抑制NK细胞对肿瘤细胞的细胞溶解活性。这些结果表明,BPTF激活肝素酶表达,从而减少细胞表面HSPGs和NCR共配体,抑制NK细胞活性。此外,来自人类乳腺癌肿瘤的基因表达数据显示,BPTF表达升高与抗肿瘤免疫细胞特征降低相关,支持BPTF在抑制抗肿瘤免疫中的保守作用。在已建立的小鼠乳腺肿瘤中,条件性BPTF耗竭可增强抗肿瘤免疫,表明抑制BPTF可能提供一种新的免疫治疗方法。引文格式:Kimberly Mayes, Zeinab Elsayed, Aiman Alhazmi, Michael Waters, Suehyb Alkhatib, Mark Roberts, Carolyn Song, Kristen Peterson, Vivian Chan, Nikhil Ailaney, Pumoli Malapati, Tana Blevins, Berislav Lisnic, Catherine Dumur, Joseph Landry。肿瘤细胞内禀BPTF抑制NK细胞活性和天然细胞毒性受体共配体的丰度[摘要]。摘自:AACR肿瘤免疫学和免疫治疗特别会议论文集;2017年10月1-4日;波士顿,MA。费城(PA): AACR;癌症免疫,2018;6(9增刊):摘要nr A28。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Abstract A28: Tumor cell intrinsic BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands
Using syngeneic BALB/c mouse breast cancer models, we show that the chromatin remodeling subunit bromodomain PHD finger transcription factor (BPTF) suppresses natural killer (NK) cell antitumor activity in the tumor microenvironment (TME). In culture, BPTF suppresses direct natural cytotoxicity receptor (NCR) mediated NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating conserved functions. Blocking mouse NCR1 in vivo rescues BPTF KD tumor weights, demonstrating its importance for the control of tumor growth. We discovered that BPTF occupies heparanase (Hpse) regulatory elements, activating its expression. Increased heparanase activity results in reduced cell surface abundance of the NCR co-ligands: heparan sulfate proteoglycans (HSPGs). Using gain and loss of function approaches we show that elevated heparanase levels suppress NK cell cytolytic activity to tumor cells in culture. These results suggest that BPTF activates heparanase expression, which in turn reduces cell surface HSPGs and NCR co-ligands, inhibiting NK cell activity. Furthermore, gene expression data from human breast cancer tumors shows that elevated BPTF expression correlates with reduced antitumor immune cell signatures, supporting conserved roles for BPTF in suppressing antitumor immunity. Conditional BPTF depletion in established mouse breast tumors enhances antitumor immunity, suggesting that inhibiting BPTF could provide a novel immunotherapy. Citation Format: Kimberly Mayes, Zeinab Elsayed, Aiman Alhazmi, Michael Waters, Suehyb Alkhatib, Mark Roberts, Carolyn Song, Kristen Peterson, Vivian Chan, Nikhil Ailaney, Pumoli Malapati, Tana Blevins, Berislav Lisnic, Catherine Dumur, Joseph Landry. Tumor cell intrinsic BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A28.
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