Anti-tumor immunity and intestinal microbiota are modulated by mitochondrial DNA

抗肿瘤免疫和肠道微生物群由线粒体 DNA 调节

基本信息

批准号：
10426606
负责人：
Douglas C Wallace
金额：
$ 65.41万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10426606
关键词：
Adoptive Cell Transfers Antioxidants C57BL/6 Mouse Cell Nucleus Cells Cellular Structures Cellular immunotherapy Cessation of life Clinical Clinical Services Colon Carcinoma Congenic Mice Congenic Strain Gene Expression Generations Genotype Growth Hematopoietic Human Human papillomavirus 16 Immune Immune response Immune system Immunotherapy Impairment In complete remission Ligands Link Lung Adenocarcinoma MC38 Malignant Neoplasms Mediating Medical center Mesothelioma Metabolic Metastatic Melanoma Mitochondria Mitochondrial DNA Mus Outcome Oxidative Phosphorylation Oxides PPBP gene Patients Phenotype Positioning Attribute Production Reactive Oxygen Species Refractory Regulation Resistance Risk Severities Testing Tissues Transgenes Tumor Immunity Tumorigenicity Variant Volatile Fatty Acids anti-PD-1 anti-PD-L1 anti-PD-L1 therapy anti-PD1 therapy anti-tumor immune response antioxidant enzyme antitumor effect cancer immunotherapy cancer risk catalase cell type congenic epigenome fatty acid oxidation fecal microbiota fecal transplantation gene function gut microbiota melanoma metabolomics microbiota mitochondrial genome neoplasm immunotherapy patient response programmed cell death ligand 1 receptor response transgene expression tumor tumor progression

项目摘要

Project Summary Recently, it was shown by Dr. Ben Boursi, Sheba Medical Center, that some metastatic melanoma patients who are refractory to anti-PD-1 immunotherapy can be converted to responders by fecal microbiota transfer (FMT) from a melanoma patient that had a complete response to immunotherapy. Unfortunately, other donor-recipient combinations were unsuccessful implying that an additional uncontrolled factor may determine the effects of microbiota modulation of immunotherapy. Concurrently, we have been using congenic C57BL/6 mice harboring different naturally occurring mitochondrial DNAs (mtDNAs) (mtDNAB6, mtDNA129, and mtDNANZB) to test melanoma sensitivity and anti-PD-L1 therapy. We discovered that the mtDNANZB mice are highly resistant to melanoma progression and strongly respond to anti-PD-L1 therapy, while mtDNA129 mice are permissive for melanoma growth and refractory to immunotherapy, with mtDNAB6 mice being in between. These mice also differ in their gut microbiota and metabolomic analysis of the mtDNANZB mice revealed impaired fatty acid oxidation of relevance to the elaboration of short chain fatty acids (SCFAs) by the gut microbiota. When we expressed the mitochondrially-targeted antioxidant enzyme catalase (mCAT) in the mitochondria of the mouse hematopoietic cells, we diminished the anti-tumor immune response of the mtDNANZB mice and changed the gut microbiota of both the mtDNAB6 and mtDNANZB mice. These observations led us to the hypothesis that: Both the gut microbiota and the immune system are modulated by the mitochondrial genome, in part through mitochondrial reactive oxygen species (mROS) production in immune cells linking the gut microbiota, tumor progression, and immunotherapy. To test this hypothesis, we propose three specific aims. First, we will evaluate mitochondrial function and mROS production in our three congenic strains and correlate this with their immune cell repertoire and function. Then, we will determine if these congenic strains show the same range of responses to other tumor types. Second, we will determine which subclass of hematopoietic cells are responsible for the anti-tumor and pro-immunotherapy response by using adoptive cell transfer (ACT) to replace mtDNA129 immune cells with mtDNANZB cells. We will then express mCAT in the functional immune cells to determine if this negates the anti- tumor and pro-immunotherapy response and changes their microbiota. Third, we will use FMT to replace the gut microbiota of the mtDNA129 and mtDNANZB mice with that of the three congenic strains to determine if mtDNANZB microbiota enhances the mtDNA129 anti-tumor and pro-immunotherapy phenotype and if mtDNA129 microbiota diminish the mtDNANZB phenotype. To confirm that this is mediated by mROS production, we will express mCAT in the responsible immune cells of the mtDNA129 mice and confirm that this blocks the induction of any anti-tumor and pro-immunotherapy phenotype induced by FMT from mtDNANZB mice. To expeditiously extend these findings to human mtDNA lineages and clinical service, Dr. Boursi has agreed to be a collaborator and Dr. Yardeni has arranged positions at both CMEM and Sheba.

项目摘要最近，Sheba医疗中心的Ben Boursi博士表明，一些转移性黑色素瘤患者可以通过粪便菌群转移（FMT）将抗PD-1免疫疗法难治性转化为反应者来自对免疫疗法完全反应的黑色素瘤患者。不幸的是，其他捐助者会员组合不成功，暗示一个额外的不受控制的因素可能决定了免疫疗法的微生物群调节。同时，我们一直在使用携带的Encenic C57BL/6只小鼠不同的天然线粒体DNA（mTDNA）（mtdnab6，mtdna129和mtdnanzb）进行测试黑色素瘤敏感性和抗PD-L1治疗。我们发现mtdnanzb小鼠对黑色素瘤进展并对抗PD-L1治疗有强烈反应，而MTDNA129小鼠允许使用黑色素瘤的生长和对免疫疗法的难治性，MTDNAB6小鼠介于两者之间。这些小鼠也有所不同在其肠道菌群和MTDNANZB小鼠的代谢组分分析中，发现脂肪酸氧化受损与肠道菌群对短链脂肪酸（SCFA）阐述有关。当我们表达小鼠造血的线粒体中的线粒体靶向抗氧化剂酶过氧化酶（MCAT）细胞，我们减少了mtdnanzb小鼠的抗肿瘤免疫反应，并改变了肠道菌群 MTDNAB6和MTDNANZB小鼠。这些观察结果使我们提出了以下假设：肠道菌群既是免疫系统由线粒体基因组调节，部分通过线粒体反应性与肠道菌群，肿瘤进展和免疫疗法。为了检验这一假设，我们提出了三个具体目标。首先，我们将评估线粒体在我们的三种先天性菌株中的功能和MROS产生，并将其与其免疫细胞库相关联和功能。然后，我们将确定这些先天性菌株是否显示出对其他响应的范围肿瘤类型。其次，我们将确定哪些造血细胞的亚类负责抗肿瘤通过使用收养细胞转移（ACT）来代替MTDNA129免疫细胞，并用 mtdnanzb细胞。然后，我们将在功能免疫细胞中表达MCAT，以确定这是否否定抗 - 肿瘤和促免疫疗法反应并改变其菌群。第三，我们将使用FMT替换 MTDNA129和MTDNANZB小鼠的肠道菌群具有三种先行菌株中的小鼠，以确定是否是否 mtdnanzb微生物群增强了MTDNA129抗肿瘤和促免疫疗法表型，如果MTDNA129 菌群减少mtdnanzb表型。为了确认这是由MROS生产介导的，我们将在MTDNA129小鼠的负责任免疫细胞中表达MCAT，并确认这会阻止诱导 Mtdnanzb小鼠FMT诱导的任何抗肿瘤和促免疫疗法表型。快速地将这些发现扩展到人类MtDNA谱系和临床服务，Boursi博士已同意成为合作者 Yardeni博士已在CMEM和Sheba安排职位。