更新于：2024-11-01

CD226

更新于：2024-11-01

基本信息

别名

CD226、CD226 antigen、CD226 molecule

+ [5]

简介

Involved in intercellular adhesion, lymphocyte signaling, cytotoxicity and lymphokine secretion mediated by cytotoxic T-lymphocyte (CTL) and NK cell (PubMed:8673704). Cell surface receptor for NECTIN2. Upon ligand binding, stimulates T-cell proliferation and cytokine production, including that of IL2, IL5, IL10, IL13, and IFNG. Competes with PVRIG for NECTIN2-binding (PubMed:26755705).

关联

项与 CD226 相关的药物

IMB1001

靶点

CD226

作用机制

CD226抑制剂

在研机构

Imidomics, Inc. [+2]

原研机构

TNAX Biopharma Corp.初创企业

在研适应症

克罗恩病 [+2]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

LY-3435151

靶点

CD226

作用机制

CD226抑制剂

在研机构-

原研机构

Eli Lilly & Co.

在研适应症-

非在研适应症

晚期恶性实体瘤 [+8]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 CD226 相关的临床试验

NCT04099277 / Terminated临床1期

A Phase 1a/1b Study of LY3435151 Administered to Patients With Advanced Solid Tumors

The reason for this study is to see if the study drug LY3435151 is safe in participants with advanced solid tumors.

开始日期2019-10-28

申办/合作机构

Eli Lilly & Co.

100 项与 CD226 相关的临床结果

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100 项与 CD226 相关的转化医学

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0 项与 CD226 相关的专利（医药）

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847

项与 CD226 相关的文献（医药）

2024-11-01·Neurology Neuroimmunology & Neuroinflammation

Impact of the Multiple Sclerosis-Associated Genetic Variant CD226 Gly307Ser on Human CD8 T-Cell Functions

Article

作者: Friebel, Ekaterina ; Aubert, Yann ; Nunez, Nicolas ; Masson, Frederick ; Bernard, Isabelle ; Adoue, Véronique ; Astier, Anne ; Saoudi, Abdelhadi ; Becher, Burkhard ; Dejean, Anne S. ; Morandi, Elena ; Martinet, Ludovic

BACKGROUND AND OBJECTIVESThe rs763361 nonsynonymous variant in the CD226 gene, which results in a glycine-to-serine substitution at position 307 of the CD226 protein, has been implicated as a risk factor of various immune-mediated diseases, including multiple sclerosis (MS). Compelling evidence suggests that this allele may play a significant role in predisposing individuals to MS by decreasing the immune-regulatory capacity of Treg cells and increasing the proinflammatory potential of effector CD4 T cells. However, the impact of this CD226 gene variant on CD8 T-cell functions, a population that also plays a key role in MS, remains to be determined.METHODSTo study whether the CD226 risk variant affects human CD8 T-cell functions, we used CD8 T cells isolated from peripheral blood mononuclear cell of 16 age-matched healthy donors homozygous for either the protective or the risk allele of CD226. We characterized these CD8 T cells on T-cell receptor (TCR) stimulation using high-parametric flow cytometry and bulk RNAseq and through characterization of canonical signaling pathways and cytokine production.RESULTSOn TCR engagement, the phenotype of ex vivo CD8 T cells bearing the protective (CD226-307Gly) or the risk (CD226-307Ser) allele of CD226 was largely overlapping. However, the transcriptomic signature of CD8 T cells from the donors carrying the risk allele presented an enrichment in TCR, JAK/STAT, and IFNγ signaling. We next found that the CD226-307Ser risk allele leads to a selective increase in the phosphorylation of the mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 (ERK1/2) associated with enhanced phosphorylation of STAT4 and increased production of IFNγ.DISCUSSIONOur data suggest that the CD226-307Ser risk variant imposes immune dysregulation by increasing the pathways related to IFNγ signaling in CD8 T cells, thereby contributing to the risk of developing chronic inflammation.

2024-10-01·Molecular Neurobiology

Meta-analysis of the Selected Genetic Variants in Immune-Related Genes and Multiple Sclerosis Risk

Article

作者: Zhou, Weiguang ; Ma, Xiaorui ; Qi, Meifang ; Hu, Weiqiong ; Liao, Jiaxi ; Chen, Bifeng ; Li, Jing ; Tang, Lingyu ; Yu, Zhiyan

Previous studies have suggested that certain variants in immune-related genes may participate in the pathogenesis of multiple sclerosis (MS), including rs17824933 in the CD6 gene, rs1883832 in the CD40 gene, rs2300747 in the CD58 gene, rs763361 in the CD226 gene, rs16944 in the IL-1β gene, rs2243250 in the IL-4 gene, and rs12722489 and rs2104286 in the IL-2Rα gene. However, the results remained inconclusive and conflicting. In view of this, a comprehensive meta-analysis including all eligible studies was conducted to investigate the association between these 8 selected genetic variants and MS risk. Up to June 2023, 64 related studies were finally included in this meta-analysis. The odds ratios (ORs) and corresponding 95% confidence intervals (CIs) calculated by the random-effects model were used to evaluate the strength of association. Publication bias test, sensitivity analyses, and trial sequential analysis (TSA) were conducted to examine the reliability of statistical results. Our results indicated that rs17824933 in the CD6 gene, rs1883832 in the CD40 gene, rs2300747 in the CD58 gene, rs763361 in the CD226 gene, and rs12722489 and rs2104286 in the IL-2Rα gene may serve as the susceptible factors for MS pathogenesis, while rs16944 in the IL-1β gene and rs2243250 in the IL-4 gene may not be associated with MS risk. However, the present findings need to be confirmed and reinforced in future studies.

2024-10-01·Cytometry Part A

OMIP‐106: A 30‐color panel for analysis of check‐point inhibitory networks in the bone marrow of acute myeloid leukemia patients

Article

作者: Ptacek, Antonin ; Vanikova, Sarka ; Musil, Jan

AbstractAcute myeloid leukemia (AML) is the most common form of acute leukemia diagnosed in adults. Despite advances in medical care, the treatment of AML still faces many challenges, such as treatment‐related toxicities, that limit the use of high‐intensity chemotherapy, especially in elderly patients. Currently, various immunotherapeutic approaches, that is, CAR‐T cells, BiTEs, and immune checkpoint inhibitors, are being tested in clinical trials to prolong remission and improve the overall survival of AML patients. However, early reports show only limited benefits of these interventions and only in a subset of patients, showing the need for better patient stratification based on immunological markers. We have therefore developed and optimized a 30‐color panel for evaluation of effector immune cell (NK cells, γδ T cells, NKT‐like T cells, and classical T cells) infiltration into the bone marrow and analysis of their phenotype with regard to their differentiation, expression of inhibitory (PD‐1, TIGIT, Tim3, NKG2A) and activating receptors (DNAM‐1, NKG2D). We also evaluate the immune evasive phenotype of CD33+ myeloid cells, CD34+CD38−, and CD34+CD38+ hematopoietic stem and progenitor cells by analyzing the expression of inhibitory ligands such as PD‐L1, CD112, CD155, and CD200. Our panel can be a valuable tool for patient stratification in clinical trials and can also be used to broaden our understanding of check‐point inhibitory networks in AML.

120

项与 CD226 相关的新闻（医药）

2024-10-24

·GlobeNewswire-Health Care

iTeos Therapeutics to Highlight Inupadenant Preclinical, Translational, and Phase 2 A2A-005 Clinical Trial Data in 2L NSCLC at ESMO Immuno-Oncology Congress

WATERTOWN, Mass. and GOSSELIES, Belgium, Oct. 24, 2024 (GLOBE NEWSWIRE) -- iTeos Therapeutics, Inc. (Nasdaq: ITOS) (“iTeos”), a clinical-stage biopharmaceutical company pioneering the discovery and development of a new generation of immuno-oncology therapeutics for patients, today announced that preclinical, translational, and clinical data from inupadenant will be presented at the European Society for Medical Oncology Immuno-Oncology (ESMO-IO) Congress 2024, being held December 11-13, 2024 in Geneva, Switzerland. The clinical and translational data from the dose escalation portion of A2A-005, the Phase 2 trial assessing inupadenant and platinum-doublet chemotherapy in post-immunotherapy metastatic non-small cell lung cancer (NSCLC) patients, will be presented as mini oral presentations. Preclinical data from inupadenant will be presented in the poster session. Mini Oral Presentation DetailsTitle: The A2AR Antagonist Inupadenant Promotes Humoral Responses in PatientsAbstract Number: 174MOSession Title: Mini Oral Session 1Date / Time: December 12, 2024 at 9:24 am CEST Title: Inupadenant Combined with Chemotherapy in Patients with Non-Squamous NSCLC Progressing On or After Immune Checkpoint Inhibitor Therapy: Results from Dose-Finding Part of the A2A-005 TrialAbstract Number: 120MOSession Title: Mini Oral Session 2Date / Time: December 12, 2024 at 14:55 pm CEST Poster Presentation DetailsTitle: The A2AR Antagonist Inupadenant Promotes Humoral Responses in Preclinical ModelsAbstract Number: 48PSession Title: Poster Display SessionDate / Time: December 12, 2024 at 12:30 pm CEST ESMO-IO indicates that all regular abstracts will be published on the ESMO-IO website on Thursday, December 5, 2024 at 00:05 am CEST. About iTeos Therapeutics, Inc.iTeos Therapeutics is a clinical-stage biopharmaceutical company pioneering the discovery and development of a new generation of immuno-oncology therapeutics for patients. iTeos Therapeutics leverages its deep understanding of tumor immunology and immunosuppressive pathways to design novel product candidates with the potential to restore the immune response against cancer. The Company’s innovative pipeline includes three clinical-stage programs targeting novel, validated immunosuppressive pathways designed with optimized pharmacologic properties for improved clinical outcomes, including the TIGIT/CD226 axis and the adenosine pathway. iTeos Therapeutics is headquartered in Watertown, MA with a research center in Gosselies, Belgium. About Inupadenant (EOS-850) Inupadenant is a next-generation small molecule antagonist targeting adenosine A2A receptor (A2AR), the primary receptor on immune cells whose activation by adenosine suppresses innate and adaptive immune cell responses leading to inhibition of antitumor responses. Optimized for potency, high selectivity of A2AR, and activity at high adenosine concentrations in solid tumors, inupadenant is uniquely designed with its insurmountable profile to inhibit the ATP-adenosine pathway and has the potential for enhanced antitumor activity as compared to other A2AR antagonists in clinical development. The therapeutic candidate is in Phase 2 development. Internet Posting of InformationiTeos routinely posts information that may be important to investors in the 'Investors' section of its website at www.iteostherapeutics.com. The Company encourages investors and potential investors to consult our website regularly for important information about iTeos. For further information, please contact: Investor Contact:Carl MauchiTeos Therapeutics, Inc.carl.mauch@iteostherapeutics.com Media Contact:media@iteostherapeutics.com

临床2期免疫疗法

2024-10-03

·佰傲谷BioValley

免疫衰老关键细胞

细胞是机体的基本组成单位，其发生衰老会导致低能量效应、并驱动整体衰老，免疫细胞是衰老细胞的关键调节因子，其在衰老过程中也出现功能失调。 doi: 10.1038/s41392-023-01502-8. 造血干细胞（HSC） HSC衰老是免疫衰老的基础。衰老HSC会分化为各类功能失调的免疫细胞，导致免疫衰老。衰老HSC的主要特征是自我更新、分化偏向、能量代谢改变。HSC衰老特点细胞分化偏向更偏向形成骨髓细胞，淋巴细胞减少，导致骨髓-淋巴失衡。诱导偏向的细胞因子： IL-1/3/6； TNFα； IFN； G-CSF、M-CSF、GM-CSF。能量代谢改变从无氧糖酵解转向氧化磷酸化。由此产生ROS引起氧化应激，导致DNA损伤、细胞凋亡。自我更新减弱细胞周期活性降低。中性粒细胞年龄相关疾病与中性粒细胞功能降低相关，而中性粒细胞发育、数量的改变不大。中性粒细胞衰老特点功能降低吞噬能力降低；粘附性、趋化性异常；细胞凋亡增加； NET释放异常； TLR功能异常。中性粒细胞表达CXCR2可以响应CXCL1向炎症部位迁移，但衰老的中性粒细胞CXCR2表达下调，导致其迁移功能异常，不仅使抗炎作用降低，同时会引起非炎症部位损伤。单核/巨噬巨噬细胞功能恶化是免疫衰老的一个关键因素，其清除组织中衰老细胞的能力会随年龄增加而减弱，表现自噬水平降低、抵抗病毒感染的能力缺陷。巨噬细胞衰老特点SASP表型 IL-1β、IL-6、TNFα产生增加； IL-10产生减少，导致更易纤维化。代谢改变糖酵解、线粒体OXPHOS降低，导致能量不足，细胞功能受损。细胞周期异常细胞周期检查点p16INK4a、p21CIP1表达上调。 NK细胞随年龄增长，外周血和骨髓中NK祖细胞数量未受影响，而NK总数增加，不过NK细胞增殖、杀伤能力下降。NK细胞衰老特点细胞比例改变 CD56（bright）NK减少（未成熟）； CD56（dim）NK增加（成熟）。NK激活受损NK激活受体NKp30、NKp46、DNAM1表达降低，免疫监视功能受损。细胞毒性减弱穿孔素、颗粒酶、IFNα、IFNγ产生减少； IL-1/4/6/8/10、TNFα产生增加。 B细胞生命周期中B细胞生成会持续进行，但虽年龄增长因骨髓生态位变化导致B细胞输出受影响。B细胞衰老特点比例改变骨髓前体B细胞、浆细胞减少；外周抗体反应性记忆B细胞减少，耗竭记忆B细胞增加。促炎记忆B细胞产生促炎细胞因子： IL-1α、IL-1β、IL-6、TNFα。 B细胞与年龄相关的改变也是疫苗接种后抗体反应下降的主要原因。60~75岁人群接种流感疫苗的血清阳性保护率也仅为41~58%，75岁以上人群更低为29~46%。同时B细胞多样性崩溃，各类自身抗体产生增加。 T细胞正常情况下，T细胞数量靠胸腺输出和外周幼稚T细胞增殖来维持，而随年龄增长T细胞数量失衡；而且衰老与T细胞间的关系非常微妙，衰老会引起T细胞功能障碍，功能失调的T细胞又会释放多种炎症分子加速衰老。T细胞衰老特点数量改变Treg数量增加。 Th数量增加，其中CD4幼稚T细胞PU.1、BATF、IRF4转录因子网络诱导Th9分化偏好。 CD8循环初始T细胞数量减少； CD8效应T细胞增加，BATF、IRF4促进初始T细胞向效应T细胞转化，并上调效应功能相关转录因子（T-bet、Runx3、Blimp-1）。效应功能减弱炎症水平升高Treg虽然数量增加，但抑制能力减弱，间接诱导炎症。 Th1、Th2分泌细胞因子能力减弱，免疫防御功能下降； Th9通过产生IL-9参与自身免疫性和各类炎症性疾病过程。记忆T细胞CD27、CD28共刺激分子丢失，出现耗竭表型； CD45RA+CD8+T细胞出现SASP表型，产生高水平IL-18、ADAM28，促进炎症。小结随着机体衰老，大多免疫细胞表现出衰老特征，内在表现为衰老/受损细胞清除效率降低，外在表现为免疫抵抗力减弱。而且由细胞的衰老相关分泌表型（SASP）所引起的慢性炎症不仅是衰老的结果，也是促进衰老进一步发展的重要原因，由此上升到器官、组织，最终会导致各类疾病发生。 doi: 10.1038/s41392-023-01502-8. 参考资料 Li X et al. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther. 2023;8(1):239. Published 2023 Jun 8. doi: 10.1038/s41392-023-01502-8. Yousefzadeh MJ et al. An aged immune system drives senescence and ageing of solid organs. Nature. 2021 Jun;594(7861):100-105. Mogilenko DA, Shpynov O, Andhey PS, et al. Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of Inflammaging. Immunity. 2021;54(1):99-115.e12. Hagen M, Derudder E. Inflammation and the Alteration of B-Cell Physiology in Aging. Gerontology. 2020;66(2):105-113. 本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

临床研究疫苗临床结果

2024-09-24

·生物探索

Nature｜NKp46活化ILC1放大自身免疫组织损伤

引言自身免疫病（autoimmune diseases）是机体免疫系统对自身组织器官攻击导致的炎症性疾病。自身免疫病的发病具有隐匿性、遗传倾向、难治性和复发性。常见的自身免疫病包括系统性红斑狼疮、I型糖尿病、类风湿性关节炎等。自身免疫病的发生与自身免疫耐受的打破进而引起自身反应抗体和细胞毒细胞的产生有关。然而，有意思的是，部分健康人群即使存在自身抗体，但并没有进一步发展为疾病状态，表明自身耐受的打破本身并不足以引起全面的炎症和组织损伤【1】。因此，一个关键的问题是炎症信号在自身免疫病中如何启动以及进一步放大，最终导致疾病的启始和恶化，这对于自身免疫病的治疗具有重要意义。近日，德国柏林夏里特医学院Antigoni Triantafyllopoulou研究团队在Nature上发表了文章Amplification of autoimmune organ damage by NKp46-activated ILC1的研究文章。这项研究揭示NKp46调节ILC1-巨噬细胞-肾实质细胞轴，在不影响自身免疫条件下促进肾脏炎性级联反应放大导致组织损伤，为自身免疫宿主易感的分子机制提供深层次理解以及对慢性炎症性疾病的免疫治疗有重要意义。作者首先在雌性NZB/W F1代小鼠中监测免疫细胞浸润情况。使用静脉注射CD45荧光抗体标记血管相关CD45+免疫细胞（CD45i.v.+）以区分组织浸润CD45+免疫细胞（CD45i.v.-）。NKp46作为激活型免疫受体常表达在ILC1、NK和部分黏膜ILC3（NCR+ILC3），这里统称为NKp46+ILC。流式分析发现组织NKp46+ILC在狼疮肾炎肾组织中显著增加。NK细胞表达而CD49b-ILC1和ILC3细胞并不表达CD49b和Eomes。在狼疮肾炎（lupus nephritis，LN）中，血管相关免疫细胞表型为Eomes+CD49b+，表明NK细胞；而组织浸润细胞为Eomes-CD49b-，表明CD49b-ILC1和ILC3细胞。鉴于NK细胞依赖于Eomes，而ILC1和NKp46+ILC3依赖于GATA3。作者分别在Ncr1cre/+;Eomesfl/fl小鼠观察到CD49b+细胞显著降低，而CD49b+CD45i.v.-细胞不受影响，在Ncr1cre/+;GATA3fl/fl小鼠观察到CD49b+NK细胞比例不变，而CD49b+CD45i.v.-细胞显著降低。与此同时,作者在人肾炎组织中同样观察到NKp46+ILC1和ILC3样细胞。总之，上述数据表明CD49b+NKp46+ILC是NK细胞，而组织CD49b-NKp46+ILC是ILC1或NKp46+ILC3。随后，作者探索NKp46+ILC在狼疮肾炎中的作用。虽然短期anti-asialoGM1注射有效删除组织和血管相关NKp46+ILC，但长期anti-asialoGM1注射显著降低组织而非血管相关NKp46+ILC。体内结果显示，长期anti-asialoGM1注射有效改善狼疮肾炎症状，如降低蛋白尿和血尿素氮但并不影响anti-dsDNA滴度。另外，作者发现使用NKp46封闭抗体（mNCR1.15）虽然不能清除NKp46+ILC，但杀伤和结合实验表明其可以有效阻断NKp46功能。体内结果同样显示mNCR1.15在不影响anti-dsDNA滴度条件下有效改善狼疮肾炎症状。scRNA-seq分析表明阻断NKp46逆转肾炎中足细胞的丢失和毛细血管内皮损伤。总之，上述数据表明自身免疫性组织损伤需要NKp46+ILC和NKp46信号。随后，作者分析肾组织内NKp46+ILC，包括tILC（ILC1和NKp46+ILC3）和tNK。tILC高表达ILC1基因（Thy1、Cxcr6、Cd226和Tbx21）而低表达NK相关基因（Eomes、granzymes和Klra）。肾炎中两种NK细胞富集，包括Tcf7+NK和Tigit+NK，分别代表早期分化和失能状态。tILC则主要包括Zfp683+tILC、Il7r+tILC和Il2+tILC，分别代表成熟、未成熟ILC1以及活化增殖ILC状态。值得注意的是，作者发现一种Tnfrsf9+tILC，高表达Il2ra和TNF超家族基因（例如Tnfrsf1b、Tnfrsf9、Lta和Tnfsf14）、黏附分子Icam1、趋化因子Ccl1和生长因子Csf1以及Csf2。Tnfrsf9+tILC而非其他NKp46+ILC，富集NKp46激活相关基因且在肾炎中以NKp46依赖方式增加浸润。为了确定Tnfrsf9+tILC是ILC1还是ILC3，作者分析RORγt-fate map（FM）小鼠发现Tnfrsf9+tILC大部分来源于RORγt-FM-细胞，表明NKp46刺激调控的主要是ILC1，但也会NKp46+ILC1短暂激活RORγt表达。由于NKp46+tILC低细胞毒性和前述其可以产生Csf2以及肾炎单核巨噬细胞的显著改变，作者推测NKp46+tILC的组织损伤能力可能依赖于Csf2介导的单核巨噬调节作用。首先，作者发现Tnfrsf9+tILC是肾组织唯一产生Csf2的tILC和tNK细胞，且Csf2的产生依赖于NKp46信号。其次，Csf2-tdTomato报告小鼠发现在肾小球附近，NKp46+ILC是最主要的CSF2表达细胞。另外，CSF2封闭抗体显著减轻肾炎相关的蛋白尿、尿素氮和近端肾小管上皮损伤。最后，疾病相关的巨噬细胞大部分来源于外周血单核细胞，且CSF1R封闭删除巨噬细胞抑制肾损伤。因此，上述数据表明NKp46+tILC来源的CSF2募集外周单核细胞来源的巨噬细胞介导自身免疫组织损伤。正常肾组织巨噬细胞为CD11blowMHC-IIhigh，而肾炎肾组织巨噬细胞为CD11bhighMHC-IIhigh/low。那么NKp46信号阻断如何影响疾病相关巨噬细胞呢？作者发现NKp46阻断虽然减轻肾炎症状，但没有再次恢复CD11blowMHC-IIhigh的巨噬细胞稳态表型，而只是大量减少疾病相关巨噬细胞浸润，表明NKp46+ILC通过CSF2调节疾病相关巨噬细胞扩增。随后，转录组测序分析发现狼疮肾炎相关一群TREM2+巨噬细胞，TREM2与巨噬细胞胞葬正相关，而与促炎基因负相关，表明TREM2+巨噬细胞是组织损伤的反应细胞。后续实验发现TREM2缺失导致肾小球毛细血管结构紊乱，表明TREM2在促进巨噬细胞向抗炎分化发挥作用。综上所述，这项研究通过肾脏免疫细胞和实质细胞scRNA-seq结合抗体阻断和基因敲除实验，揭示NKp46+ILC1细胞通过Csf2介导单核巨噬细胞调节放大自身免疫组织损伤，对炎症性病理损伤及其治疗具有重要意义。参考文献 1. Mahasish, Shome., Yunro, Chung., Ramani, Chavan., Jin G, Park., Ji, Qiu., Joshua, LaBaer.(2022). Serum autoantibodyome reveals that healthy individuals share common autoantibodies. Cell Rep, 39(9), 0. doi:10.1016/j.celrep.2022.110873 https://doi.org/10.1038/s41586-024-07907-x 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

免疫疗法细胞疗法