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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：
10580086
负责人：
Douglas C Wallace
金额：
$ 62.18万
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/10580086
关键词：
Adoptive Cell Transfers Agreement 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 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 immunoregulation melanoma metabolomics microbiota mitochondrial genome patient response permissiveness programmed cell death ligand 1 receptor response 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.

项目概要最近，Sheba 医疗中心的 Ben Boursi 博士表明，一些转移性黑色素瘤患者抗 PD-1 免疫疗法难治的患者可通过粪便微生物群转移 (FMT) 转化为应答者来自对免疫疗法有完全反应的黑色素瘤患者。不幸的是，其他捐赠者-受赠者组合不成功意味着额外的不受控制的因素可能会决定效果免疫疗法的微生物群调节。同时，我们一直在使用携带 C57BL/6 的同系小鼠不同天然存在的线粒体 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 小鼠则允许黑色素瘤生长且对免疫治疗耐药，mtDNAB6 小鼠介于两者之间。这些小鼠也有所不同 mtDNANZB 小鼠的肠道微生物群和代谢组学分析显示，脂肪酸氧化受损与肠道微生物群合成短链脂肪酸（SCFA）的相关性。当我们表达小鼠造血线粒体中的线粒体靶向抗氧化酶过氧化氢酶（mCAT）细胞，我们削弱了 mtDNANZB 小鼠的抗肿瘤免疫反应，并改变了小鼠的肠道微生物群 mtDNAB6 和 mtDNANZB 小鼠。这些观察结果使我们得出这样的假设：肠道微生物群免疫系统是由线粒体基因组调节的，部分是通过线粒体反应性的免疫细胞中氧物种（mROS）的产生与肠道微生物群、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，我们将评估线粒体我们的三个同源菌株的功能和 mROS 产生，并将其与它们的免疫细胞库相关联和功能。然后，我们将确定这些同源菌株是否对其他菌株表现出相同范围的反应肿瘤类型。其次，我们将确定哪个造血细胞亚类负责抗肿瘤通过使用过继细胞转移 (ACT) 来替代 mtDNA129 免疫细胞，从而产生促免疫治疗反应 mtDNANZB 细胞。然后，我们将在功能性免疫细胞中表达 mCAT，以确定这是否会抵消抗- 肿瘤和促免疫治疗反应并改变其微生物群。第三，我们将用FMT来替代将 mtDNA129 和 mtDNANZB 小鼠的肠道微生物群与三个同源品系的肠道微生物群进行比较，以确定是否 mtDNANZB 微生物群增强 mtDNA129 抗肿瘤和促免疫治疗表型，如果 mtDNA129 微生物群减少 mtDNANZB 表型。为了确认这是由 mROS 产生介导的，我们将在 mtDNA129 小鼠的负责免疫细胞中表达 mCAT，并证实这会阻止诱导 mtDNANZB 小鼠 FMT 诱导的任何抗肿瘤和促免疫治疗表型。为了尽快 Boursi 博士已同意成为合作者，将这些发现扩展到人类 mtDNA 谱系和临床服务 Yardeni博士在CMEM和Sheba均安排了职位。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Super-Resolution Imaging of Voltages in the Interior of Individual, Vital Mitochondria.

DOI：
10.1021/acsnano.3c02768
发表时间：
2024-01-16
期刊：
ACS NANO
影响因子：
17.1
作者：
Lee, ChiaHung;Wallace, Douglas C.;Burke, Peter J.
通讯作者：
Burke, Peter J.

Improved CAR-T cell activity associated with increased mitochondrial function primed by galactose.

CAR-T 细胞活性的提高与半乳糖引发的线粒体功能的增强相关。

DOI：
10.1101/2023.09.23.559091
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Gross,Golda;Alkadieri,Suha;Meir,Amilia;Itzhaki,Orit;Aharony-Tevet,Yarden;Yosef,ShaharBen;Zenab,Angi;Shbiro,Liat;Toren,Amos;Yardeni,Tal;Jacoby,Elad
通讯作者：
Jacoby,Elad