C. Reviriego, Anneliese O. Speak, Gemma Turner, V. Iyer, L. Parts, D. Adams
{"title":"Abstract B145: Identification of tumor cell intrinsic immune evasion mechanisms","authors":"C. Reviriego, Anneliese O. Speak, Gemma Turner, V. Iyer, L. Parts, D. Adams","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B145","DOIUrl":null,"url":null,"abstract":"The ability of cells of the immune system, in particular CD8+ cytotoxic T-cells and natural killer (NK) cells, to kill tumor cells in vivo is now being exploited in the clinic with the advent of immunotherapy. While these therapies are effective in a subset of patients the emergence of tumor resistance is now being observed in the clinic. Several studies have investigated tumour evasion from CD8+ cytotoxic T-cell directed killing; however, it is not known if the same mechanisms apply for the tumor cells to evade NK cells. For instance, one major pathway of CD8+ cytotoxic T-cell resistance is via alteration of the MHC class I antigen presentation pathway which could in theory allow the tumor cells to become more sensitive to NK cell mediated killing due to “loss of self.” We have investigated tumor cell intrinsic NK cell resistance and sensitivity pathways using genome-wide CRISPR-Cas9 loss of function in vitro screens. These screens have confirmed the essential role of cell adhesion via ICAM1 in enabling tumor cell killing by NK cells. We have also identified other novel pathways that could be manipulated to enhance tumor cell cytotoxicity and the development of alternative and/or additive therapeutic strategies in the clinic. Citation Format: Carmen Ballesteros Reviriego, Anneliese O. Speak, Gemma Turner, Vivek Iyer, Leopold Parts, David J. Adams. Identification of tumor cell intrinsic immune evasion mechanisms [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B145.","PeriodicalId":120683,"journal":{"name":"Other Topics","volume":"129 1","pages":"0"},"PeriodicalIF":0.0000,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Other Topics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B145","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
The ability of cells of the immune system, in particular CD8+ cytotoxic T-cells and natural killer (NK) cells, to kill tumor cells in vivo is now being exploited in the clinic with the advent of immunotherapy. While these therapies are effective in a subset of patients the emergence of tumor resistance is now being observed in the clinic. Several studies have investigated tumour evasion from CD8+ cytotoxic T-cell directed killing; however, it is not known if the same mechanisms apply for the tumor cells to evade NK cells. For instance, one major pathway of CD8+ cytotoxic T-cell resistance is via alteration of the MHC class I antigen presentation pathway which could in theory allow the tumor cells to become more sensitive to NK cell mediated killing due to “loss of self.” We have investigated tumor cell intrinsic NK cell resistance and sensitivity pathways using genome-wide CRISPR-Cas9 loss of function in vitro screens. These screens have confirmed the essential role of cell adhesion via ICAM1 in enabling tumor cell killing by NK cells. We have also identified other novel pathways that could be manipulated to enhance tumor cell cytotoxicity and the development of alternative and/or additive therapeutic strategies in the clinic. Citation Format: Carmen Ballesteros Reviriego, Anneliese O. Speak, Gemma Turner, Vivek Iyer, Leopold Parts, David J. Adams. Identification of tumor cell intrinsic immune evasion mechanisms [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B145.
随着免疫疗法的出现,免疫系统细胞,特别是CD8+细胞毒性t细胞和自然杀伤(NK)细胞在体内杀死肿瘤细胞的能力正在被临床利用。虽然这些疗法对一部分患者有效,但现在在临床中观察到肿瘤耐药性的出现。一些研究调查了CD8+细胞毒性t细胞定向杀伤的肿瘤逃避;然而,是否同样的机制适用于肿瘤细胞逃避NK细胞尚不清楚。例如,CD8+细胞毒性t细胞抵抗的一个主要途径是通过MHC I类抗原呈递途径的改变,从理论上讲,这可能使肿瘤细胞对NK细胞介导的杀伤变得更加敏感,因为“自我丧失”。我们在体外筛选中使用全基因组CRISPR-Cas9功能缺失研究了肿瘤细胞内在NK细胞抗性和敏感性途径。这些筛选证实了通过ICAM1细胞粘附在NK细胞杀伤肿瘤细胞中的重要作用。我们还发现了其他新的途径,可以被操纵来增强肿瘤细胞的细胞毒性,并在临床中开发替代和/或附加治疗策略。引文格式:Carmen Ballesteros Reviriego, Anneliese O. Speak, Gemma Turner, Vivek Iyer, Leopold Parts, David J. Adams。肿瘤细胞内在免疫逃避机制的鉴定[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约,纽约。费城(PA): AACR;癌症免疫学杂志2019;7(2增刊):摘要nr B145。