Defining cellular and molecular mechanisms underlying cancer immunotherapy-induced autoinflammatory syndromes.

定义癌症免疫治疗诱导的自身炎症综合征的细胞和分子机制。

• 批准号: 2060451
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2060451
• 关键词: Defining; cellular; molecular; mechanisms; underlying

Checkpointinhibitors(CPIs)aretransformingtreatmentofseveralsolidtumours(1).Therationalefortheirmechanismcentreson breakingimmunetolerancetotumourantigenstoenableeffectorTcellstokilltumourcells.Thisisachievedbyinhibitingimmune checkpointmolecules(suchasCTLA-4andPD-1)onT cellstoovercomeimmunesuppression(2).Alimitation ofthesetherapiesis the emergence of a range of autoinflammatory syndromes, collectively termed immune-related adverse events (IRAEs), that phenocopy a range of autoimmune diseases (3). IRAEs can affect any organ or tissue but most frequently target skin, gastrointestinal,endocrineandmusculoskeletalsystems.Theycanbesevereorevenfatal(4-5)andincidenceishigh(e.g.incidence of any grade IRAEs targeting multiple organs in a cohort of patients (N=175) receiving CPI therapy in the Cancer Centre at Guy's and St Thomas' NHS Foundation Trust (GSTFT) is65%).IRAEs phenocopy several autoimmune diseases suggesting IRAEs and these diseases may share pathogenic mechanisms resulting inlossoftolerance(6).StudyofIRAEsmaythusyieldopportunisticdiscoveriesintheaetiologiesofautoimmunediseases.Further, some studies have associated IRAE incidence with improved survival outcomes for cancer patients receiving CPI therapy (7-8), suggesting mechanistic links between IRAEs and anti-cancer immunity. However, the cellular and molecular drivers of IRAEs are currently undetermined. Guidance for treatment of IRAEs is suspension of CPI therapy until resolution (4) hence IRAE treatment has the potential to hinder CPI efficacy, in addition to presenting a risk to patientsthemselves.The Pathobiology of Adverse Immune Reactions (PAIR) Study is an active prospective cohort study collecting longitudinal blood samples from GSTFT patients receiving CPIs for treatment of several cancer types for mechanistic studies of IRAEs. The proposed project seeks to probe PAIR Study samples to elucidate the earliest phenotypic changes in peripheral immune cell populations induced by CPIs, and to determine whether detection of these changes at their earliest detectable stage could allow for identification of biomarkers of IRAE risk. We thus aim to address both critical scientific and clinical needs surrounding IRAEs. Preliminary data from our lab suggest serum levels of several soluble inflammatory mediators may indicate likelihood of IRAE development, and that mass cytometry can be used to track immune cell phenotypic changes across serial bloodsamples of PAIR Study subjects to study CPI-induced changes. These data support our proposed experimental approach and hypotheses (see below).My experimental goals are to:1.DeeplyphenotypeperipheralimmunecellpopulationspresentinPAIRpatientPBMCsamplesusingmasscytometryalongside unsupervised data analysis techniques to identify (a) the earliest CPI-induced phenotypic changes and (b) differences in the baseline immune cell phenotypes of patients experiencing different grades ofIRAEs.2.Validate identified cell populations using flowcytometry.3.Functionally characterise effector populations that may be drivingIRAEs.4.Test whether CPI treatment of baseline PBMC samples in vitro can induce cellular and molecular responses observed in vivo, and whether these responses are augmented in samples from patients who proceed to developIRAEs.

检查点抑制剂（CPI）正在改变几种实体瘤的治疗方法（1）。其治疗机制主要是破坏对肿瘤抗原的免疫耐受，使效应T细胞能够抑制肿瘤细胞。这是通过将免疫检查点分子（如CTLA-4和PD-1）粘附在T细胞上来克服免疫抑制来证实的（2）。这些治疗的一个局限性是出现一系列自身炎性综合征，统称为免疫相关不良事件（IRAE），其表型模仿一系列自身免疫性疾病（3）。IRAE可以影响任何器官或组织，但最常见的靶向皮肤，胃肠道，内分泌和肌肉系统。它们可以是致命的（4-5）和不可逆的高（例如，在Guy's and St托马斯' NHS Foundation Trust（GSTFT）癌症中心接受CPI治疗的患者队列（N=175）中，靶向多个器官的任何级别IRAE的发生率为65%）IRAE表型复制了几种自身免疫性疾病，提示IRAE和这些疾病可能具有导致耐受性丧失的致病机制（6）。IRAE的研究可能因此在自身免疫性疾病的病因学中产生机会性的发现。此外，一些研究已经将IRAE发生率与接受CPI治疗的癌症患者的改善的存活结果相关联（7-8），表明IRAE和抗癌免疫之间的机械联系。然而，IRAE的细胞和分子驱动因素目前尚未确定。IRAE的治疗指南是暂停CPI治疗直至消退（4），因此IRAE治疗除了对患者自身造成风险外，还可能阻碍CPI疗效。不良免疫反应病理学（PAIR）研究是一项积极的前瞻性队列研究，从接受CPI治疗的GSTFT患者中收集纵向血液样本，用于IRAE的机制研究。拟议项目旨在探测PAIR研究样本，以阐明CPI诱导的外周免疫细胞群体的最早表型变化，并确定在最早可检测阶段检测这些变化是否可以识别IRAE风险的生物标志物。因此，我们的目标是解决围绕IRAE的关键科学和临床需求。来自我们实验室的初步数据表明，几种可溶性炎症介质的血清水平可能表明IRAE发展的可能性，并且可以使用质谱细胞术来跟踪PAIR研究受试者的系列血液样本中的免疫细胞表型变化，以研究CPI诱导的变化。这些数据支持我们提出的实验方法和假设（见下文）。我的实验目标是：1.使用流式细胞术和无监督数据分析技术，在PAIR患者PBMC样本中检测表型外周免疫细胞群，以确定（a）CPI诱导的最早表型变化和（B）经历不同级别IRAEs患者的基线免疫细胞表型差异。2.使用流式细胞术检测细胞群。3.功能性抑制可能驱动IRAEs的效应细胞群。4.测试体外基线PBMC样本的CPI治疗是否可以诱导体内观察到的细胞和分子应答，以及这些反应是否在发生IRAE的患者样本中增强。

项目成果

Acute Immune Signatures and Their Legacies in Severe Acute Respiratory Syndrome Coronavirus-2 Infected Cancer Patients.

• DOI: 10.1016/j.ccell.2021.01.001
• 发表时间: 2021-02-08
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Abdul-Jawad S;Baù L;Alaguthurai T;Del Molino Del Barrio I;Laing AG;Hayday TS;Monin L;Muñoz-Ruiz M;McDonald L;Francos Quijorna I;McKenzie D;Davis R;Lorenc A;Chan JNE;Ryan S;Bugallo-Blanco E;Yorke R;Kamdar S;Fish M;Zlatareva I;Vantourout P;Jennings A;Gee S;Doores K;Bailey K;Hazell S;De Naurois J;Moss C;Russell B;Khan AA;Rowley M;Benjamin R;Enting D;Alrifai D;Wu Y;Zhou Y;Barber P;Ng T;Spicer J;Van Hemelrijck M;Kumar M;Vidler J;Lwin Y;Fields P;Karagiannis SN;Coolen ACC;Rigg A;Papa S;Hayday AC;Patten PEM;Irshad S
• 通讯作者: Irshad S