更新于：2024-11-01

FLCN

更新于：2024-11-01

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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665

项与 FLCN 相关的文献（医药）

2024-10-01·Oncotarget

Molecular chaperones: Guardians of tumor suppressor stability and function

Review

作者: Heritz, Jennifer A. ; Backe,, Sarah J. ; Mollapour, Mehdi

The term 'tumor suppressor' describes a widely diverse set of genes that are generally involved in the suppression of metastasis, but lead to tumorigenesis upon loss-of-function mutations. Despite the protein products of tumor suppressors exhibiting drastically different structures and functions, many share a common regulatory mechanism-they are molecular chaperone 'clients'. Clients of molecular chaperones depend on an intracellular network of chaperones and co-chaperones to maintain stability. Mutations of tumor suppressors that disrupt proper chaperoning prevent the cell from maintaining sufficient protein levels for physiological function. This review discusses the role of the molecular chaperones Hsp70 and Hsp90 in maintaining the stability and functional integrity of tumor suppressors. The contribution of cochaperones prefoldin, HOP, Aha1, p23, FNIP1/2 and Tsc1 as well as the chaperonin TRiC to tumor suppressor stability is also discussed. Genes implicated in renal cell carcinoma development-VHL, TSC1/2, and FLCN-will be used as examples to explore this concept, as well as how pathogenic mutations of tumor suppressors cause disease by disrupting protein chaperoning, maturation, and function.

2024-09-19·Orphanet journal of rare diseases

Clinical and genetic characteristics of 100 consecutive patients with Birt-Hogg-Dubé syndrome in Eastern Chinese region.

Article

作者: Ryu, Jay H ; Liu, Jinli ; Hu, Daiju ; Chen, Xianmeng ; Wang, Rui ; Xiao, Jun ; Hu, Xiaowen ; Jiang, Xianliang

BACKGROUNDAlthough an increasing number of patients with Birt-Hogg-Dubé syndrome (BHD) are being recognized in China, clinical and genetic characteristics are not well-defined. In addition, revised diagnostic criteria for the Chinese population was proposed in 2023, we aimed to explore their utility in clinical practice at a rare lung disease center.METHODSWe retrospectively analyzed the data of 100 consecutive patients with BHD diagnosed according to the revised Chinese BHD criteria, encountered at the First Affiliated Hospital of University of Science and Technology of China from Jan 2017 to June 2023.RESULTSThere were 100 patients (including 63 females) from 65 unrelated families in Eastern China, mostly Anhui Province. The common manifestations were pulmonary cysts (99%), pneumothorax (60%), and skin lesions (77%). Renal cancer and renal angiomyolipoma were detected in 5 patients each. 37% of patients had no family history of BHD. In total, 25 FLCN germline mutations were detected, including 6 novel mutations. In addition to hotspot mutation c.1285delC/dupC (17%), the most common mutations were c.1015 C > T (16%), c.1579_1580insA (14%), and exons 1-3 deletion (11%) in FLCN. Higher risk of pneumothorax was associated with exons 1-3 deletion mutation and c.1177-5_1177-3de1CTC compared to the hotspot mutation c.1285dupC (91% [95% CI: 0.31, 46.82, p = 0.015] and 67% [95% CI: 0.35, 71.9, p = 0.302] vs. 30%, respectively). The average delay in diagnosis was 7.6 years after initial symptoms. Chinese diagnostic criteria were mostly consistent with typical pulmonary presentations with supportive genetic evidence.CONCLUSIONIn the Eastern Chinese region, patients with BHD present most commonly with pulmonary cysts associated with pneumothorax and skin lesions. However, low incidence of renal cancer along with unexpected renal angiomyolipoma was observed. Genotypic spectrum differed from that reported from other global regions, and genotype association of pneumothorax warrants further research. The revised Chinese criteria for BHD seem more appropriate in diagnosing BHD in Chinese patients.

2024-09-09·International journal of cancer

Identification of novel candidate predisposing genes in familial nonmedullary thyroid carcinoma implicating DNA damage repair pathways.

Article

作者: Cavaco, Branca M ; Pojo, Marta ; Santos, Catarina ; Cabrera, Rafael ; Moura, Margarida M ; Rosário, Francisco ; Saramago, Ana ; Vicente, João B ; Marques, Inês J ; Lousa, Diana ; Pires, Carolina ; Bandeiras, Tiago M ; Teixeira, Manuel R ; Leite, Valeriano

The genetic basis of nonsyndromic familial nonmedullary thyroid carcinoma (FNMTC) is still poorly understood, as the susceptibility genes identified so far only account for a small percentage of the genetic burden. Recently, germline mutations in DNA repair-related genes have been reported in cases with thyroid cancer. In order to clarify the genetic basis of FNMTC, 94 genes involved in hereditary cancer predisposition, including DNA repair genes, were analyzed in 48 probands from FNMTC families, through targeted next-generation sequencing (NGS). Genetic variants were selected upon bioinformatics analysis and in silico studies. Structural modeling and network analysis were also performed. In silico results of NGS data unveiled likely pathogenic germline variants in 15 families with FNMTC, in genes encoding proteins involved in DNA repair (ATM, CHEK2, ERCC2, BRCA2, ERCC4, FANCA, FANCD2, FANCF, and PALB2) and in the DICER1, FLCN, PTCH1, BUB1B, and RHBDF2 genes. Structural modeling predicted that most missense variants resulted in the disruption of networks of interactions between residues, with implications for local secondary and tertiary structure elements. Functional annotation and network analyses showed that the involved DNA repair proteins functionally interact with each other, within the same DNA repair pathway and across different pathways. MAPK activation was a common event in tumor progression. This study supports that rare germline variants in DNA repair genes may be accountable for FNMTC susceptibility, with potential future utility in patients' clinical management, and reinforces the relevance of DICER1 in disease etiology.

项与 FLCN 相关的新闻（医药）

2024-09-22

·生物探索

Mol Cell | 谭小军团队揭示STING的原始功能在于溶酶体生成

引言人体拥有多种天然免疫系统，以保证我们能抵抗病原体感染。其中，cGAS（cyclic GMP-AMP synthase，cGAMP synthase）- STING（stimulator of interferon genes）天然免疫通路主要负责识别在细胞质中暴露的非正常DNA。最近10年，cGAS-STING通路受到了学术界和临床的高度关注，近日还获得了拉斯克基础医学奖。因为越来越多的证据表明，这条通路不仅会在感染时被激活，在包括癌症、细胞衰老和神经退行性病变等诸多其他生理病理条件下，也会被激活。其背后的原因有多种，包括内源DNA的泄漏，STING的激活突变，或者STING的降解途径失调等。活化的STING会强烈上调干扰素驱动的抗病毒反应，以及多种细胞因子驱动的炎症反应。虽然STING在宿主对抗微生物和癌症方面发挥关键作用，但在衰老和退行性疾病中STING的慢性激活反而会促进疾病发生。因此，全面理解cGAS-STING信号通路的分子机制和功能对相关疾病的防治至关重要。值得注意的是，STING在干扰素和炎症方面的功能都来自于它对TBK1激酶的直接招募和激活，而只有脊椎动物的STING才进化出了执行这些功能的模块。然而，cGAS-STING信号通路高度保守。cGAS在细菌中有多种同源基因，而STING在昆虫和软体动物中也已经存在。那么，在STING进化出干扰素和炎症的功能之前，这个通路为什么重要？为什么多种看似毫不相关的细胞功能失调都能激活cGAS-STING？既然原始的cGAS-STING不能激活炎症，那么他们对细胞失调作出何种反应？这些功能在哺乳动物和人类中是否被保留，有什么生理意义？近年来，STING在扰素和炎症以外的功能，有诸多报道。但哪些功能是STING的直接原始功能，一直是天然免疫领域悬而未决的重大问题。最近，麻省理工学院的Nir Hacohen团队和匹兹堡大学的谭小军（Jay Xiaojun Tan）团队，分别报道了STING的质子通道功能。谭小军团队发现，STING的质子通道功能高度保守，它的出现早于其在扰素和炎症方面的活性。STING的质子通道直接导致其转运小泡的质子丢失，pH升高，进而激活质子泵以及“非经典自噬”。“非经典自噬”是个容易被误解的术语，其实它不是自噬，只是自噬蛋白ATG8被直接脂质化，从而链接在了质子泵所在的单层膜上，与拥有双层膜的自噬体无关。因此，非经典自噬，又名质子泵和ATG16L1介导的LC3脂质化(V-ATPase-ATG16l1-induced LC3 lipidation, VAIL)，或者单层膜上的ATG8脂质化（conjugation of ATG8 to single membranes, CASM）。既然非经典自噬不是自噬，那么，它的功能是什么，STING激活非经典自噬的生理意义在哪里？ 2024年9月19日，匹兹堡大学医学院细胞生物学系衰老研究所谭小军团队在Molecular Cell期刊上发表了题为A TBK1-independent primordial function of STING in lysosomal biogenesis 的研究论文。在这篇文章中，作者通过质谱筛选和生物信息学分析，发现了TFEB的激活是STING的一个全新重要功能，确认了这一功能在不同物种中的高度保守性，揭示了STING的质子通道功能在TFEB激活中的核心作用，阐明了非经典自噬中的GABARAP脂质化是STING-TFEB通路中的关键步骤，证明了STING通过TFEB的转录功能激活溶酶体生物合成以增强细胞稳态，并进一步发现了STING-TFEB通路在STING慢性激活状态下对于细胞抗压能力和生存能力的重要作用（图1）。TFEB作为溶酶体生成和自噬的关键转录因子，非常原始且高度保守。在进化上，TFEB等位基因的出现远早于脊椎动物，当然也远早于STING的干扰素和炎症功能的出现。近年来，TFEB和溶酶体在免疫中的作用逐渐被揭示并成为共识。因此，TFEB的激活以及溶酶体的生成，作为STING的重要原始功能，非常合理，其必然在原始天然免疫中发挥重要作用。STING的慢性激活在正常衰老和各种老年病中普遍存在，而STING-TFEB通路在这些情况下对于细胞的生存和抗压至关重要，因此这些发现对于衰老相关疾病的治疗具有重要指导意义。图1. 溶酶体生成是STING的一项重要原始功能（Credit: Molecular Cell）为了寻找被STING激活的新转录因子，作者首先通过生物素无差别标记所有细胞质蛋白，在激活STING后分离出细胞核，随后进一步纯化出生物素标记的核蛋白（图2）。这一设计是为了找到所有受STING信号驱动后，从细胞质进入细胞核的蛋白。通过质谱分析，作者找到了一些已知会入核的STING下游蛋白，然而其中并没有发现新的转录因子，甚至没有STING下游最知名的干扰素调节因子3（IRF3），说明该筛选方法缺乏足够的灵敏度，未能挖掘出所有从胞质入核的蛋白。但是，研究者注意到，在检测到的入核蛋白中，14-3-3β非常靠前，而且它的入核能够被其他方法验证。14-3-3通常直接结合磷酸化蛋白，并将他们锁定在细胞质中以抑制这些蛋白的活性。此前的研究表明，14-3-3β所结合蛋白的去磷酸化可驱动14-3-3β入核。因此，STING的激活似乎导致了很多14-3-3β结合蛋白的去磷酸化。这与已知的STING下游TBK1激酶介导的经典磷酸化信号恰恰相反。通过一些列生物信息学分析，研究者从1000多个已知的14-3-3β结合蛋白中找到了17个通过去磷酸化而被激活的转录因子。通过检验他们的入核情况，作者发现TFEB等转录因子在STING激活以后会入核，而TFEB的一个抑制蛋白c-Myc则反之。这些结果表明，TFEB可能被STING激活了。鉴于TFEB在溶酶体生成、自噬和天然免疫方面的重要作用，作者决定进一步探究TFEB作为STING效应蛋白的可能性。图2. 生物素标记追踪蛋白入核（Credit: Molecular Cell）通过多种途径验证，研究者发现，TFEB及其家族另一位成员TFE3是cGAS-STING天然免疫通路的重要且保守的效应蛋白。cGAS、cGAMP和STING是细胞质DNA激活TFEB/TFE3的必要成分。在多种没有内源性STING的细胞系中，稳定表达STING之后，可以重建STING-TFEB通路。值得一提的是，非洲爪蟾STING没有TBK1招募模块，因此其在干扰素和炎症方面的功能并不存在。然而，不仅人类和小鼠的STING可以激活TFEB，非洲爪蟾的STING也同样可以。因此，TFEB/TFE3的激活是cGAS-STING通路的一项原始功能（图3）。进一步研究证实，STING导致的TFEB激活，依赖于STING的胞内转运，但完全独立于TBK1。图3. TFEB的激活是cGAS-STING通路的一项保守功能（Credit: Molecular Cell）接下来，研究者进一步探索阐明了STING激活TFEB/TFE3的核心机制（图4）。作者发现，他们先前报道的STING质子通道，介导了TFEB/TFE3激活。STING的质子通道，通过中和STING转运小泡的酸性pH，触发质子泵（V-ATPase）介导的单层膜上ATG8脂质化（CASM）。ATG8家族包括三个LC3基因和三个GABARAP基因；其中GABARAP脂质化为STING激活TFEB/TFE3提供了重要支撑。作者进一步发现，GABARAP的脂质化，通过抑制FLCN-FNIP-RagC/D信号轴从而阻止mTORC1介导的TFEB/TFE3磷酸化。因此，STING-GABARAP信号轴主要作用于mTORC1下游，选择性地抑制其对TFEB/TFE3的磷酸化活性。图4. STING-TFEB通路的关键机制及抑制手段（Credit: Molecular Cell）随后，作者分析了STING激活TFEB的潜在生物学意义。通过RNA测序，作者发现STING激活了溶酶体和自噬基因的转录表达。这些结果得到了qRT-PCR实验的验证。同时，细胞生物学实验证明，STING的激活能显著增加溶酶体数量。因此，STING触发了独立于TBK1的转录反应，从而上调溶酶体和自噬小体的生物合成。 TFEB和cGAS-STING通路都与细胞衰老紧密相关。在多种衰老模型中，通过cGAS-STING通路引起的无菌性炎症对于诱导衰老，及衰老相关分泌表型（senescence associated secretion phenotype，SASP）至关重要。TFEB/TFE3的激活和随后的溶酶体生成在维持衰老细胞的生存中起关键作用。由于慢性、无菌的cGAS/STING信号在衰老及老年病中很常见，作者探究了TFEB/TFE3是否维持细胞在此背景下的稳态。在STING被持续慢性激活期间，野生型细胞停止生长，而TFEB/TFE3双敲除细胞则迅速死亡。与TFEB/TFE3双敲除细胞类似，通过各种不同的遗传突变手段破坏STING-TFEB信号轴以后，细胞在STING慢性激活时，也会迅速死亡。这些数据表明，STING-TFEB通路在慢性STING激活病理条件下，对于细胞的应激和存活至关重要。这类似于衰老细胞依赖于TFEB来抵抗细胞应激并维持生存。在未来的研究工作中，作者计划利用小鼠模型来进一步验证STING-TFEB这一通路并评估其对衰老和老年疾病的影响。综上所述，该研究发现TFEB介导的溶酶体生成是STING的重要原始功能（图5）。该功能独立于TBK1激酶介导的干扰素上调和炎症反应。STING质子通道引发的GABARAP脂质化是TFEB激活的核心机制。STING-TFEB通路提高细胞的应激生存能力，对衰老相关疾病具有重要意义。图5. TFEB介导的溶酶体生成是STING的重要原始功能（Credit: Molecular Cell）参考文献 https://doi-org.libproxy1.nus.edu.sg/10.1016/j.molcel.2024.08.026 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

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