Linking the microbiome and immune-checkpoint in melanoma by RNF5
RNF5 连接黑色素瘤中的微生物组和免疫检查点
基本信息
- 批准号:9302010
- 负责人:
- 金额:$ 60.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-15 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAffectAgeAgingAnimalsAntibiotic TherapyAntibioticsAntibodiesAttenuatedAutophagocytosisBacterial TranslocationCD4 Positive T LymphocytesCD8B1 geneClinical ManagementClinical TrialsCombined Modality TherapyCytotoxic T-Lymphocyte-Associated Protein 4DataDendritic CellsDevelopmentFoundationsGlutamineGrowthHousingImmuneImpairmentInfiltrationLifeLigandsLinkMalignant NeoplasmsMediator of activation proteinMetabolismModalityModelingMonitorMouse StrainsMusMyelogenousMyeloid CellsOutcomePDCD1LG1 genePatientsPhenotypePhysiologicalPlayPredispositionRegulationRoleSmall IntestinesStressT cell regulationT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticTumor-Infiltrating LymphocytesVolatile Fatty Acidsbasegut microbiomegut microbiotaimmune checkpointimprovedinsightlymph nodesmacrophagemelanomamicrobiomemicrobiotamigrationmutantnovelnovel therapeuticspatient stratificationreceptorresponsesextargeted treatmenttumortumor growthtumor microenvironmentubiquitin ligase
项目摘要
Project Summary
This application is set to define a novel mechanism underlying the control of gut microbiota-immune checkpoint
interactions by the ubiquitin ligase RNF5, and the implications of such regulation to melanoma development
and response to therapy. Despite the most exciting and significant advances made in clinical management of
melanoma via the immune-checkpoint based clinical trials, mechanisms underlying their control, the
susceptibility to distinct therapies (or not), are among the fundamental questions that remain unsolved. Here,
we provide data to support a model whereby immune checkpoints are regulated by gut microbiome, which is
defined by the ubiquitin ligase RNF5. Our discovery of impaired growth of Braf/Pten mutant melanoma in
syngeneic Rnf5–/– mice, compared with Rnfwt littermates, was linked with enhanced infiltration of tumor-
infiltrating lymphocytes (TILs) (CD4 and CD8 positive), macrophages and dendritic cells in the tumors that
developed significantly slower in the Rnf5–/– mice. Strikingly, co-housing the Rnf5–/– and Rnfwt animals or
antibiotic ablation of the gut microbiota resulted in loss of the above phenotypes—tumor growth was no longer
attenuated and immune checkpoint-based phenotypes were largely lost. Assessment of the gut microbiome
revealed a distinct subset of bacterial species, which distinguish Rnf5–/– mice from their WT littermates (all
“pure” in-house maintained C57BL/6 strain). Notably, common to the distinct RNF5-microbiome are bacterial
species that generate select subset of short chain fatty acids. These observations provide the foundation for
our hypothesis that RNF5 controls the intestinal microbiota that affects immune checkpoint
mechanisms, which in turn impacts melanoma development. Our proposed studies will (i) define RNF5
effect on the gut microbiome–tumor interactions, (ii) identify microbiome-dependent changes in the regulation
of tumor immune checkpoint control by RNF5, and (iii) establish the physiological significance and impact of
RNF5 control of microbiome and immune checkpoint on melanomagenesis in different mouse strains, age, and
under select combination therapies. Our highly integrated studies will define the fundamental mechanisms that
underlie the regulation of both gut microbiome and immune checkpoints, thereby providing new insights into
therapeutic modalities for melanoma and other cancers.
项目概要
该应用旨在定义一种控制肠道微生物群免疫检查点的新机制
泛素连接酶 RNF5 的相互作用,以及这种调节对黑色素瘤发展的影响
以及对治疗的反应。尽管在临床管理方面取得了最令人兴奋和重大的进展
黑色素瘤通过基于免疫检查点的临床试验、其控制机制、
对不同疗法的敏感性(或不敏感性)是尚未解决的基本问题之一。这里,
我们提供数据来支持免疫检查点受肠道微生物组调节的模型,该模型是
由泛素连接酶 RNF5 定义。我们发现 Braf/Pten 突变黑色素瘤生长受损
与 Rnfwt 同窝小鼠相比,同基因 Rnf5–/– 小鼠与肿瘤浸润增强有关
肿瘤中的浸润淋巴细胞 (TIL)(CD4 和 CD8 阳性)、巨噬细胞和树突状细胞
Rnf5–/– 小鼠的发育明显较慢。引人注目的是,共同饲养 Rnf5–/– 和 Rnfwt 动物或
抗生素消除肠道微生物群导致上述表型丧失——肿瘤生长不再
减毒和基于免疫检查点的表型大部分丢失。肠道微生物群评估
揭示了细菌物种的一个独特子集,它将 Rnf5–/– 小鼠与其 WT 同窝小鼠(所有
“纯”内部维护的 C57BL/6 菌株)。值得注意的是,不同 RNF5 微生物组的共同点是细菌
产生短链脂肪酸的选定子集的物种。这些观察结果为
我们的假设是 RNF5 控制影响免疫检查点的肠道微生物群
机制,进而影响黑色素瘤的发展。我们提出的研究将 (i) 定义 RNF5
对肠道微生物组与肿瘤相互作用的影响,(ii) 确定微生物组依赖性调节变化
RNF5 控制肿瘤免疫检查点的作用,以及 (iii) 确定 RNF5 的生理意义和影响
RNF5 对不同小鼠品系、年龄和黑色素瘤生成的微生物组和免疫检查点的控制
根据选择的联合疗法。我们高度综合的研究将定义基本机制
是肠道微生物组和免疫检查点调节的基础,从而提供了新的见解
黑色素瘤和其他癌症的治疗方式。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Linda Mac Pherson Bradley其他文献
Linda Mac Pherson Bradley的其他文献
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{{ truncateString('Linda Mac Pherson Bradley', 18)}}的其他基金
Targeting Checkpoint Inhibition in Anti-Tumor Responses
抗肿瘤反应中针对检查点抑制
- 批准号:
10202111 - 财政年份:2021
- 资助金额:
$ 60.36万 - 项目类别:
Targeting Checkpoint Inhibition in Anti-Tumor Responses
抗肿瘤反应中针对检查点抑制
- 批准号:
10372199 - 财政年份:2021
- 资助金额:
$ 60.36万 - 项目类别:
Regulation of CD4+ T cell responses during chronic viral infection
慢性病毒感染期间 CD4 T 细胞反应的调节
- 批准号:
10197841 - 财政年份:2020
- 资助金额:
$ 60.36万 - 项目类别:
Regulation of CD4+ T Cell Responses During Chronic Viral Infection
慢性病毒感染期间 CD4 T 细胞反应的调节
- 批准号:
10322954 - 财政年份:2020
- 资助金额:
$ 60.36万 - 项目类别:
Frontiers in Fundamental and Translational Immunology
基础和转化免疫学前沿
- 批准号:
10318101 - 财政年份:2018
- 资助金额:
$ 60.36万 - 项目类别:
Linking the microbiome and immune-checkpoint in melanoma by RNF5
RNF5 连接黑色素瘤中的微生物组和免疫检查点
- 批准号:
10098006 - 财政年份:2017
- 资助金额:
$ 60.36万 - 项目类别:
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
- 批准号:
9308643 - 财政年份:2017
- 资助金额:
$ 60.36万 - 项目类别:
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
- 批准号:
9447149 - 财政年份:2017
- 资助金额:
$ 60.36万 - 项目类别:
Linking the microbiome and immune-checkpoint in melanoma by RNF5
RNF5 连接黑色素瘤中的微生物组和免疫检查点
- 批准号:
9445426 - 财政年份:2017
- 资助金额:
$ 60.36万 - 项目类别:
PSGL-1, a New Player in the Immune Checkpoint Landscape
PSGL-1,免疫检查点领域的新参与者
- 批准号:
9312782 - 财政年份:2016
- 资助金额:
$ 60.36万 - 项目类别:
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