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：
10098006
负责人：
Linda Mac Pherson Bradley
金额：
$ 60.36万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10098006
关键词：
Ablation Address Affect Age Aging Animals Antibiotic Therapy Antibiotics Antibodies Antitumor Response Attenuated Autophagocytosis Bacterial Translocation CD4 Positive T Lymphocytes CD8B1 gene CTLA4 gene Clinical Management Clinical Trials Combined Modality Therapy Data Dendritic Cells Development Foundations Glutamine Growth Housing Immune Impairment Infiltration Life Ligands Link Malignant Neoplasms Mediator of activation protein Metabolism Modality Modeling Monitor Mouse Strains Mus Myelogenous Myeloid Cells Outcome Patients Phenotype Physiological Play Predisposition Regulation Role Small intestine mucous membrane T cell regulation T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Tumor-Infiltrating Lymphocytes Volatile Fatty Acids bacteriome base draining lymph node endoplasmic reticulum stress gut microbiome gut microbiota immune checkpoint improved insight macrophage melanoma melanomagenesis microbiome microbiome composition microbiota microbiota profiles migration mucosal microbiota mutant novel novel therapeutics patient stratification programmed cell death ligand 1 programmed cell death protein 1 receptor response sex targeted treatment tumor tumor growth tumor microbiome tumor microenvironment ubiquitin 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。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引人注目的是，将 Rnf5-/- 和 Rnfwt 动物共同饲养时，Rnf5-/- 小鼠的发育速度显着减慢。抗生素消除肠道微生物群导致上述表型丧失——肿瘤生长不再肠道微生物组的减毒和基于免疫检查点的表型大部分丢失。揭示了细菌种类的一个独特子集，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，不同的 RNF5 微生物组的共同点是细菌。这些观察结果为产生短链脂肪酸的特定子集的物种提供了基础。我们的假设是 RNF5 控制影响免疫检查点的肠道微生物群我们提出的研究将 (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在选定的联合疗法下，我们的高度综合研究将确定其基本机制。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。