更新于：2024-09-19

FLCN

更新于：2024-09-19

基本信息

别名

BHD、BHD skin lesion fibrofolliculoma protein、Birt-Hogg-Dube syndrome protein

+ [5]

简介

Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, PubMed:31704029, PubMed:31672913, PubMed:34381247). GTPase-activating protein that plays a key role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, PubMed:31704029, PubMed:31672913). Regulates glycolysis by binding to lactate dehydrogenase LDHA, acting as an uncompetitive inhibitor (PubMed:34381247). Activates mTORC1 by acting as a GTPase-activating protein: specifically stimulates GTP hydrolysis by RRAGC/RagC or RRAGD/RagD, promoting the conversion to the GDP-bound state of RRAGC/RagC or RRAGD/RagD, and thereby activating the kinase activity of mTORC1 (PubMed:24095279, PubMed:31704029, PubMed:31672913). The GTPase-activating activity is inhibited during starvation and activated in presence of nutrients (PubMed:31672913). Acts as a key component for mTORC1-dependent control of the MiT/TFE factors TFEB and TFE3, while it is not involved in mTORC1-dependent phosphorylation of canonical RPS6KB1/S6K1 and EIF4EBP1/4E-BP1 (PubMed:21209915, PubMed:24081491, PubMed:31672913). In low-amino acid conditions, the lysosomal folliculin complex (LFC) is formed on the membrane of lysosomes, which inhibits the GTPase-activating activity of FLCN, inactivates mTORC1 and maximizes nuclear translocation of TFEB and TFE3 (PubMed:31672913). Upon amino acid restimulation, RRAGA/RagA (or RRAGB/RagB) nucleotide exchange promotes disassembly of the LFC complex and liberates the GTPase-activating activity of FLCN, leading to activation of mTORC1 and subsequent cytoplasmic retention of TFEB and TFE3 (PubMed:31672913). Indirectly acts as a positive regulator of Wnt signaling by promoting mTOR-dependent cytoplasmic retention of MiT/TFE factor TFE3 (PubMed:31272105). Required for the exit of hematopoietic stem cell from pluripotency by promoting mTOR-dependent cytoplasmic retention of TFE3, thereby increasing Wnt signaling (PubMed:30733432). Acts as an inhibitor of browning of adipose tissue by regulating mTOR-dependent cytoplasmic retention of TFE3 (By similarity). Involved in the control of embryonic stem cells differentiation; together with LAMTOR1 it is necessary to recruit and activate RRAGC/RagC and RRAGD/RagD at the lysosomes, and to induce exit of embryonic stem cells from pluripotency via non-canonical, mTOR-independent TFE3 inactivation (By similarity). In response to flow stress, regulates STK11/LKB1 accumulation and mTORC1 activation through primary cilia: may act by recruiting STK11/LKB1 to primary cilia for activation of AMPK resided at basal bodies, causing mTORC1 down-regulation (PubMed:27072130). Together with FNIP1 and/or FNIP2, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy (PubMed:25126726). Required for starvation-induced perinuclear clustering of lysosomes by promoting association of RILP with its effector RAB34 (PubMed:27113757).

关联

项与 FLCN 相关的药物

ALS(Genetic Leap)

靶点

FLCN

作用机制

FLCN modulators

在研机构

Genetic Leap

原研机构

Genetic Leap

在研适应症

肌萎缩侧索硬化

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

FLCN-ASO(Genetic Leap)

靶点

FLCN

作用机制

FLCN modulators

在研机构

Genetic Leap

原研机构

Genetic Leap

在研适应症

肌萎缩侧索硬化

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

100 项与 FLCN 相关的临床结果

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100 项与 FLCN 相关的转化医学

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0 项与 FLCN 相关的专利（医药）

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662

项与 FLCN 相关的文献（医药）

2024-07-01·Diabetes/Metabolism Research and Reviews

Fasting pancreatic polypeptide predicts incident microvascular and macrovascular complications of type 2 diabetes: An observational study

Article

作者: Bewick, Gavin A. ; Murphy, Kevin G. ; Lessan, Nader G. ; Meeran, Karim ; Bloom, Stephen R. ; Barakat, Maha T. ; Bech, Paul R. ; Yeo, Giles S. H. ; Sam, Amir H. ; Lam, Brian Y. H. ; Buckley, Adam J.

AbstractAimsPancreatic polypeptide (PP) is elevated in people with vascular risk factors such as type 2 diabetes or increased visceral fat. We investigated potential relationships between PP and microvascular and macrovascular complications of diabetes.Materials and MethodsAnimal study: Subcutaneous PP infusion for 4 weeks in high fat diet mouse model. Retinal mRNA submitted for Ingenuity Pathway Analysis. Human study: fasting PP measured in 1478 participants and vascular complications recorded over median 5.5 (IQR 4.9–5.8) years follow‐up.ResultsAnimal study: The retinal transcriptional response to PP was indicative of cellular stress and damage, and this footprint matched responses described in previously published studies of retinal disease. Of mechanistic importance the transcriptional landscape was consistent with upregulation of folliculin, a recently identified susceptibility gene for diabetic retinopathy. Human study: Adjusting for established risk factors, PP was associated with prevalent and incident clinically significant retinopathy (odds ratio (OR) 1.289 (1.107–1.501) p = 0.001; hazard ratio (HR) 1.259 (1.035–1.531) p = 0.0213), albuminuria (OR 1.277 (1.124–1.454), p = 0.0002; HR 1.608 (1.208–2.141) p = 0.0011), and macrovascular disease (OR 1.021 (1.006–1.037) p = 0.0068; HR 1.324 (1.089–1.61), p = 0.0049), in individuals with type 2 diabetes, and progression to diabetes in non‐diabetic individuals (HR 1.402 (1.081–1.818), p = 0.0109).ConclusionsElevated fasting PP is independently associated with vascular complications of diabetes and affects retinal pathways potentially influencing retinal neuronal survival. Our results suggest possible new roles for PP‐fold peptides in the pathophysiology of diabetes complications and vascular risk stratification.

2024-07-01·Molecular Genetics & Genomic Medicine

A novel variant in the FLCN gene in a Chinese family with Birt–Hogg–Dubé syndrome

Article

作者: Gu, Yufeng ; Qu, Le ; Zhou, Wenquan ; He, Haowei ; Ge, Silun ; Miao, He ; Zhou, Yulin

AbstractBackgroundThis study aimed to identify disease‐causing variants within a Chinese family affected by Birt–Hogg–Dubé syndrome (BHDS), which arises from an autosomal dominant inheritance pattern attributed to variants in the folliculin (FLCN) gene, recognized as a tumor suppressor gene.MethodsA Chinese proband diagnosed with BHDS due to renal tumors underwent next‐generation sequencing (NGS), revealing a novel variant in the FLCN gene. Sanger sequencing was subsequently performed on blood samples obtained from family members to confirm the presence of this variant.ResultsA novel germline frameshift variant (NM_144997.5:c.977dup) was identified in five individuals among the screened family members, marking the first report of this variant. Additionally, a somatic frameshift variant (NM_144997.5:c.1252del) was detected in the renal tumors of the proband. No variant was detected in unaffected family members.ConclusionsA novel heterozygous variant was identified in exon 9 of the FLCN gene, which broadens the spectrum of FLCN variants. We recommend that molecular analysis of the FLCN gene be performed in patients with suspected BHDS and their families.

2024-05-01·Seminars in Diagnostic Pathology

Birt-Hogg-Dubé syndrome in an overall view: Focus on the clinicopathological prospects in renal tumors

Review

作者: Lu, Jian ; Lu, Min ; Wu, Jialong ; Wu, Chin-Lee

Birt-Hogg-Dubé syndrome (BHD) represents a rare autosomal dominant tumor predisposition syndrome characterized by skin lesions, lung cysts, and renal tumors. The predominant histological subtypes of BHD-related renal tumors include hybrid oncocytoma-chromophobe tumors, oncocytomas, and chromophobe renal cell carcinomas, all exhibiting eosinophilic/oncocytic features. Immunohistochemistry staining for KIT (CD117) and CK7 exhibits variability in these tumor types. Germline mutations in FLCN have been consistently identified. Generally, patients with BHD demonstrate a favorable prognosis with minimal metastatic potential. Nonetheless, the comprehensive elucidation of pathological characteristics of BHD remains incomplete, particularly in BHD-associated renal tumors that deviate from the previously identified subtypes, thereby complicating the differential diagnosis. In this review, we provide a comprehensive overview of BHD encompassing epidemiology, clinical manifestations, genetic and molecular pathogenesis, as well as clinical diagnostic modalities. Emphasis is placed on clinicopathological features, specifically focusing on BHD-associated renal tumors. Collectively, this review aims to present the latest insights into BHD which benefits in the early detection, therapeutic decision-making, and prognosis prediction in BHD cases, and deepen the understanding of sporadic renal tumors.

项与 FLCN 相关的新闻（医药）

2023-07-10

·药明康德

前沿 | 补充这种氨基酸，能让免疫细胞打赢癌细胞！《自然》新研究揭示抗癌的关键营养素

▎药明康德内容团队编辑免疫疗法的发展为癌症治疗带来了巨大飞跃，其基本思路是通过激发患者自身免疫系统的力量对抗肿瘤。例如，免疫检查点阻断疗法通过阻断癌细胞发送给免疫细胞的“刹车”信号，解除肿瘤微环境对免疫细胞的抑制。不过，免疫检查点阻断疗法目前还只能让一部分患者受益，因此很多研究者正在寻找增强免疫疗法抗癌活性的新方法。日前，美国圣裘德儿童研究医院（St. Jude Children's Research Hospital）迟洪波课题组在《自然》杂志上刊发最新研究，揭示了癌细胞与免疫细胞争夺的一种关键营养素——谷氨酰胺（glutamine）。研究结果表明，直接向肿瘤提供谷氨酰胺，可帮助免疫系统提高抗癌活性，与免疫检查点阻断疗法相结合时显著遏制肿瘤生长。为了生存，肿瘤在汲取营养方面可谓非常贪婪。在肿瘤微环境中，癌细胞和免疫细胞需要争夺营养。谷氨酰胺就是微环境中的一种主要营养素。当谷氨酰胺不幸被癌细胞垄断，一种名为树突状细胞（dendritic cell）的免疫细胞就会“饿肚子”。树突状细胞作为高效的抗原呈递细胞，是激活抗癌T细胞的重要助手。而树突状细胞缺乏谷氨酰胺时，抗肿瘤免疫功能就会大打折扣。图片来源：123RFT细胞具有直接的癌细胞杀伤活性，常被看作肿瘤免疫疗法中的主角。然而，它们并不能靠单打独斗就对付癌细胞，在这项新研究中，科学家们强调了激活T细胞的树突状细胞在肿瘤微环境中的角色。迟洪波教授在圣裘德儿童研究医院的新闻稿中打了一个容易理解的比方：“我们可以将树突状细胞视为驾驶员，将T细胞视为汽车。如果没有司机，汽车无法移动。此外，谷氨酰胺等营养素相当于司机的驾照。”在肿瘤小鼠中，研究人员通过直接注射的方式向瘤内补充谷氨酰胺后，观察到小鼠的肿瘤生长得到抑制。不仅如此，补充谷氨酰胺还可以提高免疫检查点抑制剂或过继性T细胞疗法的效果。▲瘤内补充谷氨酰胺可促进cDC1介导的抗肿瘤免疫（图片来源：参考资料[1]）此外，研究人员还确定了一种分子途径，可以作为潜在的药物靶点来达到给树突状细胞补充谷氨酰胺的效果。他们发现，有两种蛋白质，FLCN和SLC38A2，是树突状细胞感知并摄取谷氨酰胺所必需的，如果免疫细胞缺少这两种蛋白，在补充谷氨酰胺的情况下也不能有效激活T细胞。这些结果提示，它们或可作为药物靶点用于提升癌症疗法的效果。“除了加强治疗干预外，我们通过展示营养素如何介导细胞之间的通讯还提供了先进的概念，这是在免疫代谢领域尚且研究不足的一个概念。”迟洪波教授指出。参考资料：[1] Chuansheng Guo et al., (2023) SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity. Nature Doi: https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-023-06299-8[2] Immune and tumor cell “tug-of-war” controls anti-cancer activity. Retrieved July 6, 2023 from https://www.eurekalert.org/news-releases/994641本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~

免疫疗法细胞疗法

2023-07-05

·Science Daily

Immune and tumor cell 'tug-of-war' controls anti-cancer activity

Scientists have found that altering amounts of the nutrient glutamine in the tumor microenvironment could enhance or impair the immune system's anti-cancer response. Scientists at St. Jude Children's Research Hospital found immune and tumor cells compete over glutamine, a major nutrient in their local environment, with significant implications for anti-cancer activity. If cancer cells monopolize glutamine, they can prevent immune cells from destroying cancer. The findings show that supplying glutamine directly to tumors helps initiate the immune system's cancer-killing activity. The researchers also identified a molecular pathway that could serve as a potential drug target to achieve the same effect. The findings were published today in Nature. "It's a nutrient tug-of-war between tumor cells and immune cells," said corresponding author Hongbo Chi, Ph.D., St. Jude Department of Immunology. "If tumor cells use all the available glutamine, then a specialized immune cell type known as the dendritic cell is starved of glutamine, leading to impaired anti-tumor immune function. But if we can supplement enough glutamine to the tumor microenvironment, that will inhibit tumor growth because dendritic cells will use it and activate the adaptive immune response." Dendritic cells turn on cancer-killing immune cells called T cells. The group showed that resupplying glutamine in the tumor microenvironment severely reduced tumor growth because dendritic cells were then better able to activate anti-cancer T cells. The tumor microenvironment is composed of chemicals and cells around cancer cells. Infamously, cancer cells secrete many signals to turn the immune response "off" in this area, especially the T cells that threaten their destruction. The St. Jude team is the first to identify a nutrient as a major signal between cancer cells and dendritic cells in this local environment. Improving anti-cancer therapies "We are very excited to establish the link between glutamine, therapeutic effect and dendritic cells," said first author Chuansheng Guo, Ph.D., St. Jude Department of Immunology. "It's critical for the efficacy of immune checkpoint blockade and adoptive cell transfer therapy." Immune checkpoint blockade therapy inhibits the "off" signals cancer cells send to immune cells that suppress the immune response in the tumor microenvironment. These therapies have been highly effective, but only in a small number of patients. The researchers found that supplying glutamine in combination with checkpoint therapy enhanced anti-cancer activity in mice. "This paper provides a proof of concept that nutrients could act synergistically with checkpoint inhibitors for tumor treatment as a new strategy for combination therapy," Chi said. The mechanism of helping or hindering cancer-killing While much cancer research has focused on T cells because of their direct cancer-killing activity, this study is one of the first to examine how the tumor microenvironment affects the dendritic cells, which activate T cells. The researchers found that without glutamine, dendritic cells failed to activate the T cells that directly kill cancer cells. "Even though T cells are the cornerstone for anti-cancer immunity, they cannot do the job by themselves," Chi explained. "We can think of dendritic cells as the driver and the T cell as the car. If you do not have a driver, the car will not move. Moreover, nutrients like glutamine serve as the license for the driver." Similarly, when the researchers removed the proteins that respond to or take up glutamine in dendritic cells, the immune cells failed to activate cancer-killing cells. These proteins, called FLCN and SLC38A2, are important in sensing and acquiring nutrients but have not previously been connected to immune cells' reactions to tumors. They may serve as potent drug targets to improve cancer therapy. "We're extremely excited about these findings," Chi said. "In addition to enhancing the therapeutic intervention, we have provided a conceptual advance by showing how nutrients mediate cell-cell communication, an understudied concept in the field of immunometabolism." The study's other authors are Zhiyuan You, Hao Shi, Gustavo Palacios, Cliff Guy, Sujing Yuan, Nicole Chapman, Seon Ah Lim, Xiang Sun, Jordy Saravia, Sherri Rankin, Yogesh Dhungana, of St. Jude, and Yu Sun and Xingrong Du, formerly of St. Jude. The study was supported by grants from the National Institutes of Health (AI105887, AI131703, AI140761, AI150241, AI150514 and CA253188) and ALSAC, the fundraising and awareness organization of St. Jude.

免疫疗法

2022-12-21

·药明康德

2022年，100多款创新、潜在可转化靶点总整理（附下载）| 年度盘点

▎药明康德内容团队编辑本期看点[1] 涵盖115个来自不同疾病领域，具转化潜力的潜在创新靶点[2] 详细介绍15个癌症、代谢疾病、中枢神经疾病等相关靶点[3] 提供完整115个靶点列表下载地址，扫描下图二维码或点击文末“阅读原文/Read more”即可访问《自然》子刊Nature Reviews Drug Discovery曾指出，每个“first-in-class”药物的上市多有赖于创新药物靶点的发现，靶点的重要性不言可喻！在2022年，全球科研人员们在创新靶点的探索和开发上做出了诸多突破：这些靶点有的是创新癌症免疫疗法诞生的契机，有的有望提升T细胞疗法的活性，有的则有可能变革阿尔茨海默病、帕金森病、非酒精性脂肪性肝炎（NASH）等重大疾病的治疗格局……图片来源：药明康德内容团队制图药明康德内容团队盘点了在2022发布于国际知名科研期刊当中的潜力靶点，以供各位医药界的朋友们作为参考。在这篇文章中，我们优选15个值得关注的靶点做详细报道。扫描下图二维码或点击文末“阅读原文/Read more”，即可下载完整115个靶点列表。▲长按扫描二维码或点击文末“阅读原文/Read more”，即可下载完整115个靶点列表。靶点统计的详细方法请参见文末。癌症免疫疗法潜在靶点靶点：ZBP1应用：增加肿瘤免疫原性期刊 / PMID：《自然》 / 35614224发现：在癌症免疫治疗中，仅有一小部分病患会对免疫检查点抑制剂（ICB）单药疗法产生长期缓解。近期RNA编辑酶ADAR1被发现与免疫检查点抑制剂疗法抗性相关。ADAR1可通过抑制具免疫原性双链RNA（dsRNA）的产生，进而避免肿瘤对免疫检查点抑制剂产生应答。在此篇论文中，科学家发现ADAR1的突变或删除会造成Z型dsRNA（Z-RNA）的累积，进而活化Z-RNA感应蛋白ZBP1，并最终导致细胞发生RIPK3介导的坏死性凋亡（necroptosis）。由于临床上目前仍不存在ADAR1抑制剂，科学家找到了一种不受ADAR1影响而直接活化ZBP1的化合物CBL0137。通过引发细胞内生成Z-RNA，CBL0137可而有效地活化ZBP1。CBL0137可在肿瘤相关成纤维细胞（CAF）内引发ZBP1依赖性坏死性凋亡，并在黑色素瘤小鼠模型中逆转肿瘤对免疫检查点抑制剂的抗性。这些结果显示即便癌症对免疫检查点抑制剂已有耐药性，通过靶向活化ZBP1依旧可引发癌细胞的坏死性凋亡，恢复对免疫疗法的应答。靶点：COL6A3应用：不限癌种T细胞疗法靶点期刊 / PMID：Science Translational Medicine / 36044599发现：T细胞受体疗法靶向细胞内外抗原，但此抗原肽片段须在肿瘤细胞上，通过与特定人类白细胞抗原（HLA）分子结合，成为peptide-HLA（pHLA）复合体呈现，才能为T细胞所识别。因此识别在肿瘤中高度表达但在健康组织内罕见、具高度TCR亲和力的pHLA复合体为TCR疗法成功的关键之一。研究人员对约1500个肿瘤与健康组织样本（包含11种不同实体瘤）进行测试，并通过量化质谱法来分析、比较组织内pHLA复合体。在使用人工智能量化分析每个细胞中含有各种pHLA复合体拷贝数后，研究人员发现一种由HLA-A*02:01所呈现的肿瘤特异性肽片段。此片段来自编码6型胶原蛋白的COL6A3基因，其第六外显子（exon 6）因选择性剪接而产生。这种选择性剪接出现在多种实体瘤基质中，但在健康组织内却十分罕见。而根据此所识别出的pHLA复合体所设计出的TCR疗法，在带有人类肿瘤细胞的小鼠当中展现良好疗效。实验结果显示，接受此项TCR疗法小鼠的肿瘤不但生长速度减缓，且有肿瘤缩小的情形。重要的是，此疗法的耐受性良好，研究人员并未观察到此疗法对正常细胞的任何毒性。因此COL6A3选择性剪接具潜力被开发成为治疗不同种类实体瘤的T细胞疗法。靶点：MC5R应用：降低肿瘤免疫抑制期刊 / PMID：《科学》/ 35926007发现：下丘脑-垂体（hypothalamic–pituitary）能够分泌多种激素调控免疫反应，而其中有部分激素或效应分子在癌症病患中有增加的情形。研究人员发现，下丘脑-垂体能够促进髓系造血（myelopoiesis）与免疫抑制作用，进而促进肿瘤的生长。皮下肿瘤的植入会引发小鼠下丘脑活化，以及促进垂体分泌α-黑素细胞刺激素（α-MSH）。α-MSH通过作用于髓系祖细胞上的黑素皮质素受体5（MC5R）而促进髓系造血、髓系细胞累积、免疫抑制与肿瘤生长等作用。靶向MC5R的拮抗肽能够提升抗肿瘤免疫反应，以及靶向PD-1免疫疗法的疗效。值得一提的是，研究人员亦发现癌症患者血清中的α-MSH水平上升，并且与患者体内循环的髓系抑制细胞量呈正相关。这些发现显示神经内分泌通路可能参与抑制肿瘤免疫反应，以及MC5R为癌症免疫疗法的潜力靶点。图片来源：药明康德内容团队制图提升T细胞疗法抗肿瘤能力靶点：PARP11应用：增强CAR-T细胞疗法抗实体瘤效力期刊 / PMID：Nature Cancer / 35637402发现：免疫抑制性的肿瘤微环境（TME）帮助实体瘤逃避抗肿瘤免疫反应并对免疫疗法产生抗性。科学家们发现包含调节性T细胞与腺苷在内的TME因子，会下调在CD8+细胞毒性T淋巴细胞（CTL）上1型干扰素受体IFNAR1的表达，而此过程与肿瘤中CTL内所诱发表达的多腺苷二磷酸核糖聚合酶11（PARP11）有关。PARP11是产生免疫抑制性TME的调节物之一。基因敲除PARP11则可避免CTL上IFNAR1的丧失，进而增加CTL的肿瘤毒杀活性并引起IFNAR1依赖性的肿瘤生长抑制。因此通过遗传学工具调控或药物来抑制PARP11，有潜力增加嵌合抗原受体（CAR）-T细胞疗法的疗效。而通过工程化造成PARP11失活的CAR-CTL则可能增加其抗实体瘤的效力。这些发现显示PARP11在具免疫抑制性的TME中所扮演的关键角色，并概念性验证靶向此信号通路以提升免疫疗法效力的可能。靶点：cBAF应用：增强T细胞疗法抗实体瘤效力期刊 / PMID：《自然》/ 35732731发现：识别能够提升记忆T（Tmem）细胞生成的机制，对于癌症疫苗的发展与抗肿瘤免疫疗法的开发是至关重要的。研究人员通过CRISPR基因编辑技术筛选体内Tmem细胞的负调节因子时发现，许多哺乳类动物典型的BRG1/BRM相关因子（cBAF）组成扮演关键角色。这些cBAF复合体的组成对于活化的CD8+ T细胞分化成效应T（Teff）细胞是必须的，而这些Teff细胞的丧失则促使Tmem细胞在体内形成。有趣的是，研究人员发现，活化的CD8+ T细胞在进行分裂时，当子细胞同时具有高度MYC与cBAF表达时，细胞较有可能分化成Teff细胞；反之，当子细胞的MYC与cBAF表达量皆低时则细胞倾向分化成Tmem细胞。关键的是，当研究人员在初始CD8+ T细胞活化的48小时内以可能的cBAF抑制剂对小鼠进行治疗时，可以促进Tmem细胞生成，并改善T细胞输入疗法治疗小鼠结直肠癌与黑色素瘤的效果。此研究显示在T细胞分化早期调控cBAF，有潜力改善实体瘤癌症免疫疗法的效果。靶点：RASA2应用：增加T细胞疗法持续性期刊 / PMID：《自然》/ 36002574发现：由于外在抑制因子与内部抑制检查点的作用，过继性T细胞疗法在癌症治疗上的效用受到局限，而靶标基因编辑可能是克服这些限制、加强T细胞疗法的关键。通过在不同免疫抑制情形下进行CRISPR基因敲除的筛选过程，研究人员识别出能够避免T细胞功能障碍的基因。不同的筛选过程皆发现RasGTP酶激活蛋白（RasGAP）RASA2是人类T细胞内的信息检查点，其表达量会在T细胞受体经急性刺激后下降，也会随着T细胞在慢性抗原暴露下逐渐升高。基因敲除RASA2会增强MAPK信号以及CAR-T细胞面对靶标抗原时的细胞溶解能力。体外实验显示，缺乏RASA2的T细胞在经过反复肿瘤抗原刺激后，与野生组细胞相比，其活化程度、细胞因子生产量与代谢活性皆较高，并展现持续的癌细胞毒杀能力。此外，RASA2基因敲除CAR-T细胞在血癌小鼠模型的骨髓中，也较具适应优势。重要的是，在许多临床前T细胞受体（TCR）疗法与CAR-T疗法中，去除RASA2能够延长异种移植的血液与实体瘤小鼠的生存期。因此RASA2可能是增加现有T细胞疗法持续性与功能性的关键靶点。其他癌症治疗潜在靶点靶点：PKMYT1疾病：CCNE1扩增肿瘤期刊 / PMID：《自然》/ 35444283发现：细胞周期蛋白E1（CCNE1）基因的扩增常见于许多类型的肿瘤，尤其是在高分化浆液性卵巢癌、子宫癌与胃食管癌，在这些癌症中细胞周期蛋白E1的高度表达与基因组不稳定性、对靶向药物具抗性相关。科学家为找出CCNE1扩增肿瘤的治疗靶标，以基于CRISPR-Cas9的技术进行基因组的合成致死配对筛选。科学家们发现，当细胞CCNE1的表达量增加，其对PKMYT1激酶的抑制变得更为敏感。PKMYT1为周期蛋白依赖性激酶1（CDK1）的负调节物。当与吉西他滨（gemcitabine）组合使用时，针对PKMYT1所开发的口服、选择性抑制剂RP-6306可以造成CCNE1扩增肿瘤缩小。因此靶向PKMYT1为CCNE1扩增肿瘤的潜在靶点。靶点：ENDOD1疾病：同源重组缺陷&TP53突变肿瘤期刊 / PMID：Nature Communications / 35606358发现：研究人员发现非典型核酸酶ENDOD1在DNA修复机制中未曾被发现的功能。当细胞内ENDOD1基因被敲除时，ENDOD1功能的丧失会使具同源重组缺陷的细胞累积大量DNA双链断裂，引起合成致死效应。有趣的是，研究人员亦同时发现在TP53突变的肿瘤细胞中敲低ENDOD1，或在ENDOD1敲除细胞中进一步敲低p53时，皆会造成细胞内单链DNA快速累积而引起细胞死亡，因此ENDOD1与p53之间亦存在合成致死关系。而这也在动物实验中获得证实，小鼠对系统性EndoD1基因敲低具良好耐受性，然而对异种移植小鼠施以全身性靶向ENDOD1的siRNA时却会抑制其身上带有TP53突变的人类肿瘤进展。这些数据显示ENDOD1有潜力作为具癌症专一性的合成致死药物靶点。靶点：LCOR疾病：三阴性乳腺癌（TNBC）期刊 / PMID：Nature Cancer / 35301507发现：配体依赖辅阻遏物（LCOR）蛋白介导了正常与肿瘤乳腺癌干细胞的分化。虽然肿瘤干细胞（CSC）造成肿瘤异质性（heterogeneity）以及肿瘤治疗抗性，但其在免疫疗法当中所扮演的角色却鲜为人知。研究人员发现以免疫检查点抑制剂治疗TNBC会筛选出具低LCOR表达量的CSC，这些CSC的抗原呈递机制（APM）蛋白表达下降，因此会使得肿瘤对免疫攻击与免疫检查点抑制剂疗法不产生应答。科学家们发现LCOR是APM基因的转录激活蛋白，能以独立于干扰素（IFN）信息的方式与IFN刺激反应元素基序（ISRE）结合。LCOR的表达可增强肿瘤的免疫原性与对免疫检查点抑制剂的应答性。重要的是，LCOR的表达亦与TNBC患者对免疫检查点抑制剂的临床应答相关。当通过外泌体（EV）递送LCOR的mRNA并同时施以PD-L1抗体治疗时，可克服小鼠TNBC细胞对免疫检查点抑制剂的抗性并消除乳腺癌细胞的转移。这些结果显示LCOR可通过提升肿瘤APM表达，加强免疫检查点抑制剂对TNBC的疗效，是一款有力的潜在靶点。代谢相关疾病潜在靶点靶点：ASGR1疾病：高胆固醇期刊 / PMID：《自然》/ 35922515发现：高胆固醇是造成心血管疾病的重大风险之一。直至目前为止，尚无通过促进胆固醇排泄以降低胆固醇水平的药物上市。过去遗传学研究曾发现去唾液酸糖蛋白受体1（ASGR1）变异所导致的功能失去突变与低胆固醇水平和心血管疾病风险降低有关。ASGR1仅表达于肝脏内，其可介导血液中去唾液酸糖蛋白内化与在溶酶体中的降解。在此篇论文中，科学家们发现小鼠内Asgr1的缺失会稳定肝X受体α（LXRα），进而造成血清与肝脏内脂肪水平的下降——这可能是因为LXRα上调转运蛋白ABCA1与ABCG5/G8，进而促进胆固醇运输至高密度脂蛋白并分别排泄至胆汁与粪便中。重要的是，当施以小鼠靶向ASGR1中和抗体时能够促进胆固醇排泄并降低脂质水平，且与atorvastatin和ezetimibe这两个广为使用的降胆固醇药物产生协同作用。因此ASGR1为促进胆固醇排泄与降低脂质水平的潜在靶点。靶点：CD47-SIRPα疾病：NASH期刊 / PMID：Science Translational Medicine / 36417485发现：坏死性凋亡是造成肝细胞在NASH疾病死亡的机制之一，然而科学家们对于这些坏死性凋亡肝细胞（necHCs）在NASH中所扮演的角色却不清楚。研究人员发现，在患有NASH的人类与小鼠肝脏中necHCs的累积，与在necHCs表面所表达的“别吃我”CD47配体相关。此外，在肝脏巨噬细胞表面亦发现CD47受体SIRPα的表达量增加，这与所观察到巨噬细胞介导的necHCs清除受损现象一致。重要的是，当科学家以靶向CD47、SIRPα抗体治疗，或以腺相关病毒递送shCD47以沉默CD47在肝细胞的表达时，在两个由饮食引起的NASH小鼠模型上皆发现肝脏巨噬细胞增加对necHCs的清除，以及肝纤维化与肝脏星状细胞（HSC）活化的生物标志物降低。HSC活化是导致肝脏纤维化的原因之一。此外，以SIRPα抗体治疗亦可避免小鼠因CD47抗体治疗而产生的贫血副作用。这些发现显示阻断CD47-SIRPα信息通路可避免necHCs在肝脏的累积以及肝纤维化进展，是治疗NASH的潜在靶点。靶点：FLCN疾病：非酒精性脂肪性肝病（NAFLD）、NASH期刊 / PMID：《科学》/ 35420934发现：NAFLD和NASH目前为止都尚未存在有效的治疗方法，虽然mTORC1通路为潜在的靶向疗法，但对于mTORC1如何控制脂质代谢却存在着争议性的解读。研究人员发现，当通过删除RagC/D鸟苷三磷酸酶激活蛋白FLCN（即卵泡素，folliculin）来选择性地抑制小鼠内的mTORC1通路时，可以在不影响其他mTORC1靶标蛋白的情况下，促进肝脏转录因子E3（TFE3）的活化。TFE3可通过诱发脂质消耗与抑制脂肪生成，保护肝脏免于NAFLD与NASH的疾病进展。这些结果对以往看似相冲突的研究做出了解释，并识别如FLCN等mTORC1通路蛋白为潜在的NAFLD与NASH治疗靶点。图片来源：药明康德内容团队制图神经系统相关疾病潜在靶点靶点：USP11疾病：阿尔茨海默病期刊 / PMID：《细胞》/ 36198316发现：与男性相较，女性具有显著较高的tau蛋白含量，也易罹患阿尔茨海默病，但造成此现象的机制尚仍不清楚。科学家在此篇论文中揭示，X连锁泛素特异性肽酶11（USP11）能够对tau蛋白进行去泛素化，进而使tau蛋白的相关位点发生乙酰化，造成tau蛋白聚集扩大的病理现象。乙酰化的tau蛋白是阿尔茨海默病患脑部内的病理特征之一。研究人员并证实，通过遗传学删除具有tau病变小鼠模型内的usp11表达时，可以选择性地保护母鼠，减少乙酰化tau蛋白的累积、tau相关病变以及认知损害。因此抑制由USP11介导的tau蛋白去泛素化可能降低女性罹患阿尔茨海默病与tau蛋白病变的风险。靶点：GPNMB疾病：帕金森病期刊 / PMID：《科学》/ 35981040发现：通过全基因组关联分析（GWAS）相关研究，许多与帕金森病相关的基因位点已被识别，然而治疗帕金森病的靶点基因与机制仍多属未知。研究人员通过GWAS数据，以及对帕金森病风险讯号与位点特征表达定量（expression quantitative trait locus）的共定位分析发现，帕金森病相关的染色体7位点（包含rs199347）与非转移性黑色素瘤糖蛋白b（GPNMB）基因相关联。研究人员发现，在细胞内，GPNMB蛋白与α突触核蛋白（α-synuclein，aSyn）存在共定位与免疫共沉淀关系。在源自诱导多能干细胞的神经元模型中，GPNMB的丧失使得细胞无法内化aSyn原纤维，进而避免产生aSyn相关的病理现象。值得一提的是，在对731位帕金森病患者与59位对照组样本的分析后发现，帕金森患者血浆中GPNMB表达量升高，且其表达量与患者疾病严重程度相关。因此GPNMB为帕金森病的风险基因，且为开发生物标志物与疾病治疗的潜在靶点。靶点：CLEC7A疾病：阿尔茨海默病期刊 / PMID：《细胞》/ 36306735发现：遗传学研究显示小胶质细胞在阿尔茨海默病中扮演关键角色，其中小胶质细胞内TREM2-SYK信号异常与疾病发展相关。TREM2 R47H蛋白的变异与罹患阿尔茨海默病的高风险相关，这些变异的蛋白无法通过SYK激酶来活化小胶质细胞。研究人员发现，缺失SYK的小胶质细胞由于无法对Aβ斑块进行包覆，会加速小鼠大脑病变与行为障碍。CLEC7A受体可直接活化SYK激酶。当系统性递送靶向CLEC7A抗体至小鼠体内时，可活化TREM2 R47H蛋白变异小鼠内的SYK激酶，进而促进小胶质细胞活化，因此CLEC7A有可能成为阿尔茨海默病免疫疗法的新治疗选择。期待这些创新靶点的发现能够促进更多创新疗法的开发，带进临床治疗的突破，造福更多受不同疾病所苦的患者。为了方便读者朋友们了解更多信息，扫描下图二维码或点击文末“阅读原文/Read more”，即可下载完整115个靶点列表。▲长按扫描二维码或点击文末“阅读原文/Read more”，即可下载完整115个靶点列表。靶点统计的详细方法请参见文末。▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放*药明康德统计于2022年1月至11月底，发布于《自然》、《科学》、《细胞》、Cancer Cell、Nature Cancer、Nature Communications、Science Translational Medicine、Science Advances等众知名期刊，具有哺乳动物实验支持，具研究新颖性，且尚未进入临床2期（或以上）试验的创新靶点。若不符合筛选标准的潜在靶点则未纳入统计之中。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

免疫疗法细胞疗法