Dissecting the interplay between immunoglobulin G and the gut microbiome in cancer progression and metastasis

剖析免疫球蛋白 G 和肠道微生物组在癌症进展和转移中的相互作用

基本信息

批准号：
10593757
负责人：
Irina Matei
金额：
$ 23.77万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-02 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593757
关键词：
Acceleration Affect Affinity Animal Model Antibodies Antitumor Response B cell repertoire B-Lymphocyte Subsets B-Lymphocytes Cancer Control Cancer Model Cell Communication Cell physiology Cells Cessation of life Compensation Cross Presentation Data Development Disease Elderly Enhancers Germ-Free Humoral Immunities Immune Immune response Immune system Immunoglobulin G Immunoglobulins Immunologic Markers Immunologic Surveillance Immunologist Immunology Immunotherapy Impairment Infiltration Inflammation Interleukin-10 Investigation Knockout Mice Lead Malignant Neoplasms Malignant neoplasm of ovary Mediating Memory B-Lymphocyte Microbe Micrometastasis Modeling Mus Myeloid-derived suppressor cells Neoplasm Metastasis Pathway interactions Patients Phenotype Play Population Predisposition Primary Neoplasm Principal Investigator Production Prognosis Risk Role Science Shapes Specificity Therapeutic Transplantation Treatment outcome Tumor Antigens Tumor Immunity Tumor Promotion Tumor Suppression Tumor stage adaptive immune response animal facility anti-tumor immune response cancer biomarkers cancer immunotherapy cancer therapy cytotoxic CD8 T cells fighting fitness gut bacteria gut microbes gut microbiome immunoregulation improved melanoma microbial microbial products mouse model multidisciplinary neoplastic cell novel pathogen prevent recruit response sarcoma tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions tumorigenic uptake

Acceleration Affect Affinity Animal Model Antibodies Antitumor Response B cell repertoire B-Lymphocyte Subsets B-Lymphocytes Cancer Control Cancer Model Cell Communication Cell physiology Cells Cessation of life Compensation Cross Presentation Data Development Disease Elderly Enhancers Germ-Free Humoral Immunities Immune Immune response Immune system Immunoglobulin G Immunoglobulins Immunologic Markers Immunologic Surveillance Immunologist Immunology Immunotherapy Impairment Infiltration Inflammation Interleukin-10 Investigation Knockout Mice Lead Malignant Neoplasms Malignant neoplasm of ovary Mediating Memory B-Lymphocyte Microbe Micrometastasis Modeling Mus Myeloid-derived suppressor cells Neoplasm Metastasis Pathway interactions Patients Phenotype Play Population Predisposition Primary Neoplasm Principal Investigator Production Prognosis Risk Role Science Shapes Specificity Therapeutic Transplantation Treatment outcome Tumor Antigens Tumor Immunity Tumor Promotion Tumor Suppression Tumor stage adaptive immune response animal facility anti-tumor immune response cancer biomarkers cancer immunotherapy cancer therapy cytotoxic CD8 T cells fighting fitness gut bacteria gut microbes gut microbiome immunoregulation improved melanoma microbial microbial products mouse model multidisciplinary neoplastic cell novel pathogen prevent recruit response sarcoma tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions tumorigenic uptake

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项目摘要

ABSTRACT Cancer progression and metastasis account for the majority of cancer- related deaths, yet how cancer overcomes the immune system to metastasize is only beginning to be understood. The promise of immunotherapies has underscored how integral the host immune cells are in controlling cancer progression and the critical role of the gut microbiome in modulating responses to immunotherapies. However, we have yet to determine how gut microbiome-immune system interactions modulate cancer metastasis, identify gut microbes associated with metastatic risk, or shift immunotherapy paradigms to proactively attack potential metastases. Recent studies highlighted the role of B cells in immune regulation of tumor progression, as tumor- infiltrating B cells positively associated with improved responses to immunotherapies and favorable prognosis. However, the co-existence of both anti- and pro-tumorigenic B cell populations during cancer progression complicates the approach to studying the functions of tumor-infiltrating B cells. Since immunoglobulin G (IgG) antibodies mediate clearance of pathogens and tumor cells with high affinity and specificity and we recently showed that IgG antibodies target specific gut bacteria, modulating the gut microbiome at steady state, we propose a focused approach to dissect the role of humoral immunity in anti-tumor responses during tumor progression. We hypothesize that the interplay between IgG and gut microbiome will be critical in hindering well defined, sequential steps during tumor progression by shaping the tumor immune microenviroment as well as systemic anti-tumor responses. Thus, we will use a novel model of immunoglobulin G (IgG) deficiency developed by Dr. Zeng to dissect the specific role of IgG production in hindering tumor progression, independent of that of other B cell functions, and to investigate how IgG response to the tumor modulates the gut microbiome and thereby affecting anti-tumor immunity. The role of immunoglobulin G in tumor progression has not yet been systematically evaluated, especially during the pre-metastatic, micro-metastatic or macro- metastatic stages of tumor metastasis. Moreover, the interplay between the gut microbiome and B cell subsets, the development of anti-tumor humoral immunity and memory B cell repertoires remain unexplored. We propose that combining the novel animal model lacking IgG with well characterized tumor models and comprehensive phenotypic and functional characterization of relevant immune subsets will allow this interdisciplinary team to dissect the role of antibodies in cancer progression and determine how the interplay between the gut microbiome and IgG shapes anti-tumor immunity and cancer progression.

抽象的癌症的进展和转移是大多数与癌症相关的死亡，但如何癌症克服了免疫系统以转移的速度才开始理解。这免疫疗法的承诺强调了宿主免疫细胞中不可或缺的一体控制癌症的进展和肠道微生物组在调节反应中的关键作用进行免疫疗法。但是，我们尚未确定如何肠道微生物组 - 免疫系统相互作用调节癌症转移，识别与转移风险相关的肠道微生物，或转移免疫疗法范式以主动攻击潜在的转移。最近的研究强调了B细胞在肿瘤进展的免疫调节中的作用，作为肿瘤渗透B细胞与对免疫疗法的反应呈正相关，并有利的预后。然而，抗肿瘤和促肿瘤B细胞的共存癌症进展过程中的种群使研究功能的方法变得复杂肿瘤浸润的B细胞。由于免疫球蛋白G（IgG）抗体介导病原体和具有高亲和力和特异性的肿瘤细胞，我们最近表明IgG 抗体靶向特定的肠道细菌，调节稳定状态的肠道微生物组，我们提出一种集中的方法，是剖析体液免疫在肿瘤过程中抗肿瘤反应中作用的作用进展。我们假设IgG和肠道微生物组之间的相互作用在通过塑造肿瘤免疫来阻碍肿瘤进展过程中良好定义的顺序步骤微型抗毒物以及全身性抗肿瘤反应。因此，我们将使用一种新颖的模型 Zeng博士剖析IgG的特定作用的免疫球蛋白G（IgG）缺乏症阻碍肿瘤进展的产生，与其他B细胞功能无关，并且研究IgG对肿瘤的反应如何调节肠道微生物组，从而影响抗肿瘤免疫。免疫球蛋白G在肿瘤进展中的作用尚未系统地评估，尤其是在近观，微转移或宏观期间肿瘤转移的转移阶段。此外，肠道微生物组和 B细胞子集，抗肿瘤的体液免疫和记忆B细胞库的发展保持未探索。我们建议将缺乏IgG的新型动物模型与井结合在一起表征肿瘤模型以及全面的表型和功能表征相关的免疫子集将使该跨学科团队能够剖析抗体在癌症进展并确定肠道微生物组和IgG形状之间的相互作用如何抗肿瘤免疫和癌症进展。