CAMP

本文为转化医学网原创，转载请注明出处 作者：Sophia 导读： 为了逃避免疫监视，肿瘤细胞在其膜表面表达外核苷酸焦磷酸酶磷酸二酯酶 1 （ENPP1），从而降解细胞外环状 GMP-AMP （cGAMP），从而抑制干扰素基因的环状 GMP-AMP 合酶 （cGAS） 刺激物 （STING） DNA 感应途径。为了充分了解这种肿瘤隐身机制，必须确定肿瘤微环境中是否也存在其他形式的具有水解cGAMP活性的ENPP1来调节这种先天免疫途径。 2024年3月18日，上海交通大学医学院季天海、杨朝勇、吴玲玲共同通讯在《Advanced Science》上发表题为“Tumor Exosomal ENPP1 Hydrolyzes cGAMP to Inhibit cGAS-STING Signaling”的研究论文，据报道， 多种肿瘤来源的外泌体携带ENPP1，能水解细胞产生的合成2′3′-cGAMP和内源性2′3′-cGAMP，抑制免疫细胞中的cGAS-STING通路。此外，肿瘤外泌体ENPP1还可以水解与LL-37（2′3′-cGAMP的有效转运蛋白）结合的2′3′-cGAMP，以抑制STING信号传导。此外，观察到从人乳腺癌和肺癌组织中分离出的外泌体中ENPP1的高表达，肿瘤外泌体ENPP1抑制CD8+ T细胞和CD4+ T细胞的免疫浸润。 研究结果阐明了肿瘤外泌体ENPP1在cGAS-STING通路中的基本功能，进一步加深了对肿瘤细胞和免疫系统之间串扰的理解。 https://onlinelibrary.wiley.com/doi/full/10.1002/advs.202308131 研究背景 01 cGAS-STING通路是一种重要的先天免疫应答通路，在自身免疫性疾病和癌症中起着重要作用。从机理上讲，环状GMP-AMP合酶（cGAS）作为胞质DNA传感器，可以首先识别来自入侵微生物病原体或受损细胞的双链DNA（dsDNA），然后以三磷酸腺苷（ATP）和三磷酸鸟苷（GTP）为底物合成2′3′-环GMP-AMP（2′3′-cGAMP）。2′3′-cGAMP作为内源性第二信使，与干扰素基因刺激因子（STING）蛋白结合，募集坦克结合激酶1（TBK1）蛋白，激活干扰素调节因子IRF3。然后，磷酸化的 IRF3 进入细胞核并导致 I 型干扰素 （IFN） 的产生，从而启动抗癌和抗病毒的先天免疫反应。为了增强宿主的先天免疫反应，2′3′-cGAMP也可以输出到细胞外，以激活旁观者细胞中的cGAS-STING信号传导。事实上，2′3′-cGAMP 作为一种阴离子亲水分子，在依赖于病毒颗粒、细胞膜通道、SLC46A 溶质载体家族、工程跨膜 （TM） 缺陷 STING 蛋白或抗菌肽的细胞之间转移。 作为cGAS-STING通路的关键因素，了解细胞外cGAMP和转运蛋白-cGAMP复合物的命运是必要的。 截止目前，ENPP1是唯一可以水解免疫递质2′3′-cGAMP的可检测蛋白酶。然而， 除了分布在肿瘤细胞膜上的ENPP1蛋白外，肿瘤微环境中是否还存在其他形式的可以水解2′3′-cGAMP的ENPP1蛋白。 外泌体是由多种细胞类型分泌的脂质双层膜囊泡（直径 30-150 nm），携带母体细胞的各种生物活性分子（例如蛋白质和核酸）以促进细胞间通讯。事实上，研究表明，肿瘤来源的外泌体是肿瘤细胞与免疫细胞之间重要的通讯介质，也是肿瘤微环境中其他非肿瘤旁观者细胞之间的重要通讯介质，可以调节宿主的免疫反应。特别是，肿瘤来源的外泌体在调节先天免疫cGAS-STING信号转导中的作用逐渐被阐明。例如，经放射治疗的肿瘤细胞已被证明可以分泌携带dsDNA的外泌体，以激活免疫细胞中的STING。最近，信号转导接头分子 1 （STAM） 已被证明可以将活化的 STING 寡聚体转运到外泌体中并降解 STING 寡聚体以负调控 STING 信号转导。尽管这些研究表明外泌体在cGAS-STING通路的调控中起着重要作用，但 肿瘤来源的外泌体调节cGAMP的分子机制仍然未知，这限制了我们对肿瘤来源的外泌体在cGAS-STING信号通路和肿瘤免疫逃逸中的调控机制的充分认识。 研究结果 02 在此背景下，我们报道了各种肿瘤细胞衍生的外泌体携带 ENPP1 蛋白;事实上，ENPP1在这些外泌体中高度富集。我们发现肿瘤来源的外泌体可以帮助游离的 2′3′-cGAMP 激活 STING 信号传导。为了削弱外泌体介导的免疫增强，肿瘤外泌体ENPP1进一步水解细胞外2′3′-cGAMP，以抑制免疫细胞中的cGAS-STING通路。LL-37 作为一种由多种细胞类型表达的抗菌肽，已被证明是 2′3′-cGAMP 的有效转运蛋白，可以增强 cGAS-STING 信号转导的免疫反应。我们的研究还表明，肿瘤外泌体ENPP1可以有效地水解与LL-37结合的2′3′-cGAMP，从而抑制免疫细胞中的STING信号传导。事实上， 肿瘤外泌体 ENPP1 可能对任何形式的 2′3′-cGAMP 具有很强的降解活性，从而抑制 cGAS-STING 信号传导。 此外，我们的研究还表明，肿瘤外泌体ENPP1可以水解细胞产生的内源性2′3′-cGAMP，从而抑制旁观者细胞中的cGAS-STING通路。事实上， 我们观察到肿瘤外泌体在肺癌和乳腺癌患者的组织样本中表现出高 ENPP1 表达。重要的是，肿瘤外泌体ENPP1的表达水平分别与CD8+ T细胞和CD4+ T细胞浸润呈负相关。 肿瘤外泌体ENPP1介导的cGAS-STING信号通路在肿瘤微环境中水解2′3′-cGAMP和LL-37-2′3′-cGAMP的机制模型。 总体而言， 我们的研究揭示了肿瘤外泌体ENPP1通过水解2′3′-cGAMP抑制cGAS-STING信号传导的机制。 这突出了肿瘤来源的外泌体在先天免疫反应中的重要作用，并加深了我们对 ENPP1 介导的 cGAS-STING 通路的理解。 参考资料： https://onlinelibrary.wiley.com/doi/full/10.1002/advs.202308131 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情

Findings show that seborrheic dermatitis is a unique inflammatory skin disease with its own molecular signatureSuggests skin barrier disruption in seborrheic dermatitis is distinct with its own disease-specific pattern SAN DIEGO, Calif., March 09, 2024 (GLOBE NEWSWIRE) -- Arcutis Biotherapeutics, Inc. (Nasdaq: ARQT), a commercial-stage biopharmaceutical company focused on developing meaningful innovations in immuno-dermatology, highlights new research that, for the first time, reveals the gene expression profile of seborrheic dermatitis. The Arcutis sponsored research from The Kimberly and Eric J. Waldman Department of Dermatology at the Icahn School of Medicine at Mount Sinai was presented in a scientific session at the American Academy of Dermatology (AAD) annual meeting (San Diego, CA, March 8 – 12) and answers key questions on the immune response and associated skin barrier disruption of seborrheic dermatitis. “Our research group has had a longstanding interest in defining the immunological pathways that underlie many inflammatory skin diseases, such as atopic dermatitis and psoriasis, shaping our understanding of these diseases and leading to new treatments,” said Emma Guttman-Yassky, MD, PhD, the Waldman Professor of Dermatology and Immunology and Health System Chair of The Department of Dermatology, and Director of the Laboratory for Inflammatory Skin Diseases at the Icahn School of Medicine at Mount Sinai. “We are excited to have successfully employed noninvasive tape-stripping techniques developed from studying these diseases to study an understudied and undertreated inflammatory skin disease, seborrheic dermatitis. These findings will help establish the groundwork for greater understanding of this very common condition.” “The pathophysiology of seborrheic dermatitis has been poorly understood. We sought to understand the gene expression patterns in seborrheic dermatitis in order to determine if this profile is distinct from or similar to other immune-mediated skin conditions,” said Benjamin Ungar, MD, director of the Alopecia Center of Excellence and director of the Rosacea & Seborrheic Dermatitis Clinic at Mount Sinai Health System. “Our data reveal that seborrheic dermatitis has a distinct immunological molecular profile. In addition, the skin barrier disruption observed in seborrheic dermatitis has unique molecular underpinnings, primarily in the tight junction of the epithelial skin cells and lipid metabolism pathways. These findings are the first to characterize the molecular profile of seborrheic dermatitis, and they will play an important role in advancing our understanding of this common and under-treated condition.” Dr. Ungar is also an assistant professor of Dermatology at the Icahn School of Medicine at Mount Sinai. The data reported at AAD are from an observational study in which tape-strips were collected from facial lesions from 27 untreated patients with seborrheic dermatitis (Investigator’s Global Assessment score mild [IGA 2, n=400], moderate [IGA 3, n=19], severe [IGA 4, n=4]) and the facial skin of 18 healthy controls and analyzed with RNA sequencing (RNA-seq). Tape-strips are a non-invasive alternative to biopsy for transcriptome analysis and expression profiling. These data demonstrate that seborrheic dermatitis is an immune disease with a uniquely polarized profile distinct from atopic dermatitis and plaque psoriasis. In addition, skin barrier disruption is suggested by a downregulation of tight junction and lipid metabolism genes. Specific findings include: 1,374 differentially expressed genes (DEGs) were identified between seborrheic dermatitis and healthy controls (674 with increased expression, 700 with decreased expression).Strong and significant upregulation of Th17-related (i.e. IL23A, PI3, LL37) and Th22-related (i.e. IL22, S100A8, S100A12) pathways were detected in seborrheic dermatitis compared with controls.Seborrheic dermatitis also showed significant Th1 activation (OASL, STAT1, CXCL9) compared with controls.There was significant downregulation of skin barrier markers (CLDN1/8, FA2H, ELOVL3) in seborrheic dermatitis compared with controls.IGA positively correlated with immune markers, including Th1/IFNG, Th17/IL17A, and Th22/IL22 [r>0.3; P<0.1 for all] and negatively correlated with skin barrier markers (SMPD4, MGLL, PLA2G15 [r≤-0.38; P<0.05]). “Despite the high prevalence of seborrheic dermatitis, there has been little dedicated clinical or basic research into the underlying cause of this chronic, inflammatory skin disease for decades. Through this collaborative research effort, we have begun to shed some light on the pathways involved in the immune response and demonstrate that seborrheic dermatitis is clearly distinct from psoriasis or atopic dermatitis, which may help explain the clinical expression of the disease, and ultimately provide important insights into its management,” said Patrick Burnett, MD, PhD, FAAD, chief medical officer, Arcutis. “We are committed to advancing the scientific understanding of this disease through additional research and collaboration with the larger dermatology research and clinical community.” Mount Sinai has received grants from Arcutis for research conducted by Dr. Ungar and Dr. Guttman. In addition, Dr. Ungar and Dr. Guttman have served as paid consultants for Arcutis. About Seborrheic DermatitisSeborrheic dermatitis affects up to 10 million people in the United States, and is a common, chronic, and recurrent inflammatory skin disease that causes red patches covered with large, greasy, flaking yellow-gray scales, and persistent itch. Seborrheic dermatitis occurs most often in areas of the body with oil-producing (sebaceous) glands, including the scalp, face (especially on the nose, eyebrows, ears, and eyelids), upper chest, and back. About ArcutisArcutis Biotherapeutics, Inc. (Nasdaq: ARQT) is a commercial-stage medical dermatology company that champions meaningful innovation to address the urgent needs of individuals living with immune-mediated dermatological diseases and conditions. With a commitment to solving the most persistent patient challenges in dermatology, Arcutis has a growing portfolio including two FDA approved products that harness our unique dermatology development platform coupled with our dermatology expertise to build differentiated therapies against biologically validated targets. Arcutis’ dermatology development platform includes a robust pipeline with multiple clinical programs for a range of inflammatory dermatological conditions including scalp and body psoriasis, atopic dermatitis, and alopecia areata. For more information, visit www.arcutis.com or follow Arcutis on LinkedIn, Facebook, and X. Forward-Looking StatementsArcutis cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. These statements are based on the Company’s current beliefs and expectations. Such forward-looking statements include, but are not limited to, statements regarding the genetic profile and cause of seborrheic dermatitis. These statements are subject to substantial known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance, or achievements to be materially different from the information expressed or implied by these forward-looking statements. Risks and uncertainties that may cause our actual results to differ include risks inherent in our business, reimbursement and access to our products, the impact of competition and other important factors discussed in the "Risk Factors" section of our Form 10-K filed with U.S. Securities and Exchange Commission (SEC) on February 27, 2024, as well as any subsequent filings with the SEC. You should not place undue reliance on any forward-looking statements in this press release. We undertake no obligation to revise or update information herein to reflect events or circumstances in the future, even if new information becomes available. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Contacts:MediaAmanda Sheldon, Head of Corporate Communicationsasheldon@arcutis.com InvestorsLatha Vairavan, Vice President, Finance and Investor Relationslvairavan@arcutis.comDerek ColeInvestor Relations Advisory Solutionsderek.cole@iradvisory.com

近日，江苏省财政厅、省科技厅发文下达了2023年省科技计划专项资金（重点研发计划社会发展）拟立项目公示，BioBAY园内企业吉美瑞生联合苏州大学附属第一医院申报的“肺前体细胞再生修复机制及在慢阻肺治疗中的临床研究”项目获批立项。肺脏等非肿瘤疾病通常以器官损伤和组织纤维化为特征，最后以器官衰竭而告终。病程通常持续进展、不可逆转，患者因此而死亡，仅在中国就有上亿慢阻肺患者亟待治疗。本项目拟通过本团队特有的R-Clone前体细胞分离培养体系，筛选出具有自我更新和增殖能力的肺前体细胞克隆。同时结合CRISPR技术与天然抗微生物多肽LL37及核心蛋白聚糖Decorin，构建抗感染/抗纤维化的功能增强型肺前体细胞，解决慢性呼吸系统疾病中常见的感染和纤维化问题。吉美瑞生再生医学集团（Regend Therapeutics）成立于2015年，由左为教授与多名留学归国学者共同创立。公司专注于前体细胞的人体器官再生医学领域，以开发创新的细胞基因治疗产品，实现人体组织器官的修复、再生和增强为使命。公司拥有包括R-Clone®前体细胞扩增平台、MiniLung®和MiniKidney®类器官功能验证平台、FF-Clone®细胞纯化工艺、Chimera®嵌合动物构建平台等核心研发平台，并以此自主研发了全球首创First-in-class新药肺前体细胞REGEND001自体回输制剂。目前已获得国家药监局颁发的两个药物临床试验批件，用于治疗特发性肺纤维化和慢性阻塞性肺病。两个项目由国内顶尖临床团队担纲，均进入到临床Ⅱ期阶段。▌文章来源：吉美瑞生再生医学责编：赵家帅审核：任旭推荐阅读企业资讯丨茂行生物与妙顺生物签署战略合作协议企业资讯丨探索蛋白质相分离，英矽智能与剑桥大学发现靶点识别新方法企业资讯丨多家BioBAY企业研究成果将亮相2023 ESMO年会