更新于：2024-11-01

CD49b

更新于：2024-11-01

基本信息

别名

alpha 2 subunit of VLA-2 receptor、CD49 antigen-like family member B、CD49B

+ [8]

简介

Integrin alpha-2/beta-1 is a receptor for laminin, collagen, collagen C-propeptides, fibronectin and E-cadherin. It recognizes the proline-hydroxylated sequence G-F-P-G-E-R in collagen. It is responsible for adhesion of platelets and other cells to collagens, modulation of collagen and collagenase gene expression, force generation and organization of newly synthesized extracellular matrix. (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human rotavirus A. (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human echoviruses 1 and 8.

关联

项与 CD49b 相关的药物

E-7820

靶点

CD49b

作用机制

CD49b抑制剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

Vatelizumab

靶点

CD49b

作用机制

CD49b抑制剂 [+1]

在研机构

NMS Group SpA [+1]

原研机构

Glenmark Pharmaceuticals Ltd.

在研适应症

肿瘤

非在研适应症

溃疡性结肠炎 [+5]

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

项与 CD49b 相关的临床试验

NCT05024994 / Active, not recruiting临床2期IIT

A Phase II Clinical Trial of E7820 for Patients With Relapsed/Refractory Myeloid Malignancies With Mutations in Splicing Factor Genes.

The researchers are doing this study to find out whether E7820 is an effective treatment for people with relapsed/refractory myeloid cancers with mutations in splicing factor genes. Participants will have acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML).

开始日期2021-08-13

申办/合作机构

Memorial Sloan Kettering Cancer Center

[+1]

NCT02306811 / Terminated临床2期

A Long-Term Follow-up Study Assessing the Safety and Efficacy of Vatelizumab in Multiple Sclerosis (MS) Patients Who Completed Treatment in Study DRI13839

Primary Objective:
To assess the long-term safety of vatelizumab in MS patients
Secondary Objective:
To assess the long-term efficacy of vatelizumab

开始日期2015-02-01

申办/合作机构

Genzyme Corp.

NCT02222948 / Terminated临床2期

A Phase 2a/2b Double-Blind, Randomized, Placebo-Controlled Study Assessing Efficacy, Safety, and Dose-Response of Vatelizumab in Patients With Relapsing-Remitting Multiple Sclerosis (RRMS)

Primary Objectives:
To assess the efficacy of vatelizumab compared to placebo as measured by a reduction in new contrast-enhancing lesions (CELs) in relapsing remitting multiple sclerosis (RRMS) patients.
To evaluate multiple doses of vatelizumab for a dose-response.
Secondary Objectives:
To evaluate the safety and tolerability of vatelizumab compared to placebo.
To evaluate the pharmacokinetics (PK) of vatelizumab.

开始日期2014-09-01

申办/合作机构

Genzyme Corp.

100 项与 CD49b 相关的临床结果

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100 项与 CD49b 相关的转化医学

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0 项与 CD49b 相关的专利（医药）

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2,006

项与 CD49b 相关的文献（医药）

2024-11-01·Life Sciences

NADPH oxidase 1/4 dual inhibitor setanaxib suppresses platelet activation and thrombus formation

Article

作者: Jang, Joara ; Shin, Hye Ji ; Park, Ji Won ; Oh, Eun Bee ; Chang, Tong-Shin ; Yu, Hyunseong

AIMSThe production of reactive oxygen species (ROS) by NADPH oxidase (NOX) is able to induce platelet activation, making NOX a promising target for antiplatelet therapy. In this study, we examined the effects of setanaxib, a dual NOX1/4 inhibitor, on human platelet function and ROS-related signaling pathways.MATERIALS AND METHODSIn collagen-stimulated human platelets, aggregometry, assessment of ROS and Ca²⁺, immunoblotting, ELISA, flow cytometry, platelet adhesion assay, and assessment of mouse arterial thrombosis were performed in this study.KEY FINDINGSSetanaxib inhibited both intracellular and extracellular ROS production in collagen-activated platelets. Additionally, setanaxib significantly inhibited collagen-induced platelet aggregation, P-selectin exposure from α-granule release, and ATP release from dense granules. Setanaxib blocked the specific tyrosine phosphorylation-mediated activation of Syk, LAT, Vav1, and Btk within collagen receptor signaling pathways, leading to reduced activation of PLCγ2, PKC, and Ca²⁺ mobilization. Setanaxib also inhibited collagen-induced activation of integrin αIIbβ3, which is linked to increased cGMP levels and VASP phosphorylation. Furthermore, setanaxib suppressed collagen-induced p38 MAPK activation, resulting in decreased phosphorylation of cytosolic PLA₂ and reduced TXA₂ generation. Setanaxib also inhibited ERK5 activation, affecting the exposure of procoagulant phosphatidylserine. Setanaxib reduced thrombus formation under shear conditions by preventing platelet adhesion to collagen. Finally, in vivo administration of setanaxib in animal models led to the inhibition of arterial thrombosis.SIGNIFICANCEThis study is the first to show that setanaxib suppresses ROS generation, platelet activation, and collagen-induced thrombus formation, suggesting its potential use in treating thrombotic or cardiovascular diseases.

2024-11-01·Gene

Landscape of extrachromosomal circular DNAs, transcriptome, and proteome analysis reveals insights into alcoholic liver cirrhosis

Article

作者: Zhou, Junying ; Wang, Yadong ; Zhang, Xin ; Li, Yuanyuan ; Li, Fei ; Liu, Jingwen

Alcoholic liver cirrhosis (ALC) is a result of excessive and chronic alcohol consumption. Because alchol can cause DNA damage, extrachromosomal circular DNA (eccDNA) was investigated in ALC liver due to it can be a result of DNA damage. Considering eccDNA has ability to lead to genomic instability as an enhancer of gene transcription, we utilized Circle-Seq to identify differences in eccDNA profiles and gene expression patterns in liver samples obtained from ALC patients (n = 3) and healthy controls (n = 3) to investigate the role of eccDNA in the development of ALC. The abundance of eccDNA in ALC (mean = 13,349) were higher than the healthy control (mean = 11,557) without significant difference (pvalue = 0.6530). We observed 1,032 eccDNA containing genes showed higher expression in ALC patients compared to healthy controls (p < 0.05, log2FC > 1). Notably, we discovered seven genes that exhibited a significant positive correlation between eccDNA abundance and gene expression levels. These genes include A disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS2), Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C), Protein TANC1 (TANC1), Integrin alpha-2 (ITGA2), EH domain-containing protein 4 (EHD4), Phosphofurin acidic cluster sorting protein 1 (PACS1), and Neuron navigator 2 (NAV2). Through mass spectrometry proteomics, ITGA2 were found to have significantly higher abbudance in ALC. Integrins are a family of proteins plays key roles in the fibrosis development of liver. Thus, our study opens a new perspective for liver fibrosis development.

2024-10-01·International Immunopharmacology

SLC4A4 as a novel biomarker involved in immune system response and lung adenocarcinoma progression

Article

作者: Zhang, Zewei ; Quan, Siyu ; Li, Na ; Liu, Yang ; Gao, Dejun ; Wang, Yuanyuan ; Lian, Shihai ; Li, Yun ; Liu, Jianbo

BACKGROUNDAltered expression and activity of solute carrier family 4 member 4 (SLC4A4) could affect the growth, survival and metastasis of tumor cells. Currently, the role of SLC4A4 in lung adenocarcinoma (LUAD) immunotherapy and prognosis was not entirely clear.METHODSWe analyzed SLC4A4 expression in LUAD tissues and cell lines using quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. The effects of SLC4A4 overexpression on angiogenesis, cell migration, invasion, and epithelial-mesenchymal transition were examined. Public databases helped construct a risk model evaluating SLC4A4's expression on LUAD prognosis and immunotherapy response. Additionally, a xenograft model, flow cytometry, and enzyme-linked immunosorbent assay further explored SLC4A4's role in tumor immune microenvironment infiltration.RESULTSUpregulation of SLC4A4 promoted apoptosis in the LUAD cell line and significantly inhibited the migration and invasive ability of cancer cells (P<0.01). A total of 10 key genes (including SIGLEC6, RHOV, PIR, MOB3B, MIR3135B, LPAR6, KRT8, ITGA2, CPS1, and C6) were screened according to SLC4A4 expression, immune score and stromal score, and a prognostic model with good outcome was constructed (AUC values of which in the training cohort at 1,3, and 5 years reached 0.73, 0.73, and 0.72, respectively). Importantly, we demonstrated that high expression of SLC4A4 was able to increase the proliferation level and cytokine secretion of CD8+ T cells for the purpose of promoting the immune system response to LUAD.CONCLUSIONOur study revealed that SLC4A4 can serve as a prognostic indicator for LUAD, providing new insights into the treatment and diagnosis of LUAD.

项与 CD49b 相关的新闻（医药）

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.libproxy1.nus.edu.sg/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

2023-10-16

·BioSpace

Incendia Therapeutics Announces Upcoming Presentations at the European Society for Medical Oncology Congress 2023

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Incendia Therapeutics, formerly Parthenon Therapeutics, a precision oncology company discovering and developing a novel class of therapies that reprogram the tumor microenvironment (TME), today announced that it will have two poster presentations at the European Society for Medical Oncology (ESMO) Congress 2023, to be held in Madrid, Spain October 20-24, 2023. The company will present data on the expression of discoidin domain receptor 1 (DDR1) mRNA and protein across 20 tumor types and will provide a detailed overview of Incendia’s Phase 1 first-in-human clinical trial for its lead candidate PRTH-101 in patients with advanced solid tumors (NCT05753722). “The tumor microenvironment is dramatically impacted by the over expression of DDR1 and its role in the alignment of collagen fibers, which ultimately prevents immune cells from being able to directly interact with tumors,” said Laura Dillon, Vice President of Translational Medicine and Bioinformatics at Incendia. “These data presented at ESMO further highlight the potential of PRTH-101 as a first-in-class DDR1 inhibitor that may address the unmet need in the numerous cancers with high DDR1 expression.” Presentation Details: Title: High DDR1 mRNA and Protein Expression Across Human Tumor Types Correlate with Epithelial Composition of the Tumor Microenvironment Lead author: Laura Dillon, Ph.D., Vice President, Translational Medicine and Bioinformatics at Incendia Therapeutics Presentation #: 2309P Presentation Time: Saturday, October 21, 12:00 - 1:00 PM CEST (6-7 AM ET) Translational Research (agnostic) Key Highlights: DDR1 is expressed in a high proportion of tumor cells across a range of epithelial tumor types, suggesting potentially broad application of DDR1-targeted therapies. A high proportion of tumor cells (median of 0.76) expressed DDR1 across all epithelial tumor types. DDR1 expression was uniformly low in mesenchymal tumors (median of 9 cells/mm2) compared to epithelial tumors (median of 2803 cells/mm2). Moderate correlation was observed between DDR1 mRNA expression and DDR1+ cell density across tumor types (R=0.48, p<0.0001). In epithelial tumors, both DDR1 mRNA and protein expression were correlated with the percentage of epithelium (R=0.37 and 0.56, respectively; both p<0.0001), with significant variance between tumor types. Title: A Phase 1 First-in-Human Study of PRTH-101, an IgG1 Monoclonal Antibody Targeting DDR1, as a Monotherapy and Combined with Pembrolizumab in Patients with Advanced Solid Malignancies Lead author: Shiraj Sen, M.D., Ph.D., Medical Oncologist and Director of NEXT Oncology Dallas Presentation #: 1079TiP Presentation Time: Monday, October 23, 12:00 – 1:00 PM CEST (6-7 AM ET) (Investigational immunotherapy) Key Highlights: Discoidin domain receptor 1 (DDR1) is a collagen receptor that represents a promising therapeutic target due to its role in excluding lymphocytes from the tumor microenvironment (TME) by aligning collagen fibers. DDR1 expression is high in multiple cancer types and associated with worse survival. PRTH-101 is a humanized IgG1 antibody that binds to the extracellular domain of both membrane-bound and soluble DDR1. In preclinical models, PRTH-101 monotherapy resulted in disruption of aligned collagen fibers in the tumor stroma, increased infiltration of lymphocytes, and tumor growth inhibition. When PRTH-101 is combined with PD-1 inhibition, activated T cell infiltration is increased compared to PRTH-101 alone. This is a Phase 1 first-in-human study that will evaluate intravenous PRTH-101 +/- pembrolizumab in patients with advanced solid tumors. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints will be monitored and reported. The first part of the study (Ph1a) seeks to identify the maximum tolerated dose (MTD) or optimal biologic dose (OBD), of PRTH-101 to determine the recommended phase 2 dose (RP2D). The second part (Ph1b) seeks to identify the MTD or OBD of PRTH-101 in combination with pembrolizumab to determine the PRTH-101 combination RP2D. The third part (Ph1c) consists of dose expansion in disease-directed cohorts to assess the anti-tumor efficacy of PRTH-101 monotherapy and/or combination therapy. About PRTH-101 PRTH-101 is a therapeutic antibody that specifically binds to and blocks discoidin domain receptor 1 (DDR1,) a protein expressed on tumor cells that binds collagen to make a physical barrier that prevents immune cells from interacting with and attacking tumor cells. By disabling DDR1, the collagen fibers lose alignment and loosen, creating gaps in the tumor barrier, thus allowing T-cells to enter and attack the tumor. Blockade of DDR1 represents a unique approach to stimulating immune-based antitumor activity, and in preclinical models such blockade shows both single agent anti-tumor activity as well as marked augmentation of immunity enhanced by PD-1 blockade. Tumor types that express high levels of DDR1-associated collagen barriers include colorectal, ovarian, and non-small cell lung cancer. Currently, there are no approved drugs that target DDR1. About Incendia Therapeutics Incendia Therapeutics is discovering and developing a novel class of anti-cancer therapies that reprogram the tumor microenvironment (TME). Recent research has shown that the interplay between tumor cells and their surrounding TME results in the creation of barriers that markedly attenuate the immune system’s ability to attack the tumor. Based on rigorous, groundbreaking research, Incendia is developing a portfolio of drug candidates to treat select patients at the appropriate/ideal stage in disease progression. For more information visit incendia.com and LinkedIn.

临床1期免疫疗法临床结果

2023-06-01

·生物探索

敲除免疫细胞中的这个基因就能根除肿瘤，还没有副作用！癌症治疗格局会改写吗？

30多年前，美国德克萨斯州贝勒医学院的研究人员发现了一类名为类固醇受体共激活因子（steroid receptor coactivator，SRC）的蛋白质。SRC家族中的三个主要成员SRC-1、SRC-2和SRC3通过与核受体（nuclear receptor）结合，与转录因子和转录启动复合物相互作用，能够调节基因转录的启动和增强过程。最初，共激活因子被认为仅仅充当核受体和转录因子组装的一个“桥梁”，但随着研究的深入，科学家们渐渐发现，共激活因子不仅是转录的动力助推器，甚至参与了基因表达的所有子步骤，因而也就对多种生理过程具有调节作用。已经证明，SRC在转录起始、延伸、RNA剪接乃至mRNA翻译中都有发挥作用。5月30日，贝勒医学院的Bert W. O'Malley团队在PNAS上发文“Steroid receptor coactivator 3 is a key modulator of regulatory T cell–mediated tumor evasion”，表明在调节性T细胞（Tregs）中敲除SRC-3的基因，可根除小鼠身上的肿瘤并提供长期的抗癌保护。图1 研究成果（图源：[2]）多年来，O'Malley团队一直对SRC-3及其在癌症中的作用特别感兴趣。SRC-3不仅在所有人类癌症中都高度表达并对癌症的多个方面都有促进作用，在抑制身体免疫反应的Tregs中也高度表达。O'Malley团队因此怀疑Tregs中丰富的SRC-3在控制癌症进展中发挥作用，并试图研究敲除Tregs中的SRC-3基因会对癌症生长有何影响。敲除了SRC-3的Tregs面对肿瘤无往不利研究人员首先通过交叉繁殖转基因小鼠，得到了特定在Tregs中敲除SRC-3基因的小鼠。Tregs 通过多种不同机制限制效应免疫细胞增殖和功能发挥作用，Tregs功能的丧失会导致病理性慢性自身免疫性疾病，然而，这些基因工程小鼠的体重、生殖能力、血液细胞因子/趋化因子的水平等，都并未表现出在Tregs功能完全消除或使用检查点抑制剂的小鼠身上观察到的病理特征。研究人员随后将一种侵袭性乳腺癌细胞系注射到小鼠的乳腺脂肪垫中。结果观察到乳腺肿瘤在对照组小鼠中急剧生长，而在实验组小鼠身上，乳腺肿瘤在细胞注射后的第五天被观察到，但在20天后已检测不到。在排除了小鼠的背景遗传因素和他莫昔芬治疗对乳腺肿瘤生长的潜在影响后，研究人员证实Tregs中SRC-3基因的敲除导致了肿瘤的根除。图2小鼠在注射乳腺癌细胞系后肿瘤生长对比（图源：[2]）此外，不论是预防肿瘤发生，还是驱动先前存在的肿瘤消退，都可以靠在Tregs中敲除SRC-3基因实现。甚至在停止治疗后肿瘤复发的问题上，实验组小鼠也表现良好，细胞注射218天后都未检测到肿瘤复发。鉴于此，研究人员进一步测试了Tregs中SRC-3基因敲除是否对之后的新肿瘤形成具有长期抵抗，结果显示乳腺癌细胞系在肿瘤根除小鼠身上的“再注射”也无法建立新的乳腺肿瘤。研究人员使用免疫组织化学分析方法，在较早时间节点观察了尚未被完全根除的肿瘤发现，敲除了SRC-3基因的Tregs渗入了肿瘤内部。对小鼠前列腺癌模型的试验则给出了和乳腺癌模型相似的结果，即敲除了SRC-3基因的Tregs也可以根除前列腺肿瘤。敲除SRC-3如何使Tregs对肿瘤重拳出击研究人员发现，在细胞水平上，Tregs中SRC-3基因敲除的小鼠的肿瘤（消失前），相比于对照组小鼠的肿瘤，表现出广泛的细胞减少，浸润性CD4+ T细胞、CD8+ T细胞和CD49b+ NK细胞数量显著升高，肿瘤中的Foxp3+Tregs更少，表明这建立起了抗肿瘤微环境。对肿瘤进行细胞因子/趋化因子分析发现，肿瘤中Ifng和Cxcl9水平显著增加。Ifng是一种中枢促炎细胞因子，可以抑制肿瘤进展并激活CD8+ T细胞和NK细胞；Cxcl9是一种趋化因子，可招募激活CD8+和NK细胞。这表明，敲除了SRC-3基因的Tregs通过增强肿瘤中的Ifng/Cxcl9，募集CD8+和NK细胞支持抗肿瘤免疫微环境的建立。Tregs RNA分析显示，敲除SRC-3使得Tregs中的共抑制分子Tigit、Klrb1c和Klrk1的下调，这些分子能够选择性地抑制促炎性T细胞反应。有意思的是，不同于肿瘤中的Tregs，敲除SRC-3使得脾脏中的Tregs中的抗炎细胞因子如Tgf-β、Il-10和Il-35表达升高。这表明敲除SRC-3后，Tregs在脾脏和肿瘤中的分子表型非常不同，而T细胞受体的激活可能是肿瘤中诱导Ifng的关键。研究人员还发现，Ifng能够增加肿瘤细胞中的某些Tregs趋化配体，而敲除SRC-3使得Tregs中相应受体水平显著升高。这说明Ifng能够以这样一条通路发出募集Tregs到肿瘤的信号。Ifng还增加了肿瘤细胞中Cxcl9 mRNA 的表达水平。此外，相比于未改造的Tregs会抑制常规T细胞的增殖，敲除SRC-3后的Tregs不仅不再对常规T细胞“过多约束”，甚至还反过来限制未改造Tregs对常规T细胞的抑制作用。这些都说明敲除SRC-3的Tregs在根除肿瘤的过程中担任了“挑大梁”的角色。图3 模型概念（图源：[2]）新疗法是否指日可待Tregs的过继性细胞转移（Adoptive Cell Transfer，ACT）疗法常用于治疗各种慢性自身免疫性疾病，但并不适用于治疗实体癌。在这里，由于敲除了SRC-3的Tregs表现出根除肿瘤的能力以及对未改造Tregs的抑制作用，研究人员试图评估单次注射改造后的Tregs能否根除野生型小鼠身上已存在的肿瘤。结果显示，注射成功地抑制了小鼠身上的乳腺肿瘤生长，且在ACT后超过215天都未观察到肿瘤复发。对ACT治疗后尚未完全根除的肿瘤进行分析，研究人员发现，注射Tregs在肿瘤中的分布、肿瘤中其他免疫细胞的数量、Ifng/Cxcl9的水平以及小鼠肿瘤复发及对新生肿瘤的抵抗情况，均与在基因工程敲除Tregs中SRC的小鼠身上观察到的结果类似。不过，经测试，ACT治疗想要实现理想的肿瘤清除效果，对剂量有所要求。该研究的第一作者、贝勒生殖医学中心分子和细胞生物学副教授 Sang Jun Han博士表示：“当前其他疗法或多或少可以在一段时间内减轻肿瘤负担或使肿瘤消失，但通常癌症仍会复发。我们这次在动物模型上的发现则表明，敲除了SRC-3的Tregs不仅可以根除已有的肿瘤，甚至极有希望提供长久的保护防止肿瘤的复发。未来，这将可能成为癌症治疗的一个有效靶点，而且，还不会造成类似于免疫检查点抑制剂造成的自身免疫副作用。”Han表示：“我们对结果感到非常兴奋。接下来我们将继续钻研，以将这些发现转化为一种新颖、更有效、更持久的癌症疗法。”O'Malley还是生物制药公司CoRegen 的首席科学官。目前，贝勒医学院已将该研究的发现以及相关的所有专利和知识产权授权给CoRegen，希望能以此开发出一种革命性的、无副作用的癌症疗法并使之商业化。责编|风立宵校对|风立宵End参考资料：[1]York B, O'Malley BW. Steroid receptor coactivator (SRC) family: masters of systems biology. J Biol Chem. 2010 Dec 10;285(50):38743-50. doi: 10.1074/jbc.R110.193367.[2]Han, S.J., Jain, P., Gilad, Y., et al. Steroid receptor coactivator 3 is a key modulator of regulatory T cell–mediated tumor evasion. Proceedings of the National Academy of Sciences. 2023; 120(23): e2221707120. https://doi-org.libproxy1.nus.edu.sg/10.1073/pnas.2221707120[3]https://www.genengnews.com/topics/cancer/gene-elimination-in-tregs-triggers-lifelong-anticancer-response-in-mice/ [4]https://www.eurekalert.org/news-releases/990392 本文系生物探索原创，欢迎个人转发分享。其他任何媒体、网站如需转载，须在正文前注明来源生物探索。往期精选围观 ‍把病毒困在“陷阱”里！海德堡大学探明病毒渗透最后一步，或将带来预防新手段！热文基因振荡器：在两种衰老模式间来回切换，细胞寿命延长了82%！热文用超声波突破皮肤屏障！MIT科学家为皮肤给药提供可穿戴解决方案热文新发现：加速癌症发展的染色体外DNA，甚至出现在癌症之前，推动组织癌变！热文在基因组中“跳来跳去”的转座子，有望成为免疫疗法抗击肿瘤的新靶点！点击“阅读原文”，了解更多~

信使RNA寡核苷酸