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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：
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.

项目总结