Mechanism of microbiota-mediated potentiation of checkpoint blockade efficacy in lung cancer

微生物群介导的肺癌检查点阻断功效增强机制

基本信息

批准号：
10436388
负责人：
Dan Littman
金额：
$ 56.07万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10436388
关键词：
Adverse effects Antibiotic Resistance Antibiotic Therapy Antibiotics Antibodies Antigenic Specificity Autoimmune Diseases Bacteria Bacteroides Biopsy CTLA4 gene Cancer Model Cancer Patient Cannulations Cell Wall Cells Chemosensitization Clinical Research Communities Complement Consensus Cytotoxic T-Lymphocytes Diet Disease remission Distal Event Feces Genes Genetic Diseases Genetic Engineering Gnotobiotic Growth Histologic Human IRF3 gene Immune Immune Targeting Immune response Immune system Immunotherapy Implant Individual Intestines Lead Libraries Life Lipid A Lung Adenocarcinoma Lung Neoplasms Lymph Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Mediating Metagenomics Microbe Microscopic Mismatch Repair Modeling Molecular Mimicry Molecular Target Mus Mutation Myeloid Cells Normal tissue morphology Organism PD-1/PD-L1 Patients Pattern recognition receptor Peptides Plasma Polysaccharides Population Predisposition Proteins Proteomics Relapse Research Role Serum Signal Pathway Signal Transduction Solid Solid Neoplasm Specimen Stains T-Lymphocyte T-cell receptor repertoire Testing Therapeutic Tissues Toxic effect Treatment Efficacy Tumor Immunity Tumor Tissue Wild Type Mouse Work adaptive immunity anti-PD-1 anti-PD1 therapy anti-tumor immune response antitumor effect autoimmune pathogenesis autoimmune toxicity cell killing cellular targeting checkpoint therapy cohort commensal bacteria commensal microbes design experience fecal transplantation gut microbiome gut microbiota immune checkpoint blockade immunogenic immunogenicity improved in vitro testing insight lung cancer cell mesenteric lymph node mesenteric lymphatics metabolomics microbial microbiome microbiota microorganism antigen mouse model neoantigens neoplastic cell pre-clinical programmed cell death ligand 1 rational design reconstitution responders and non-responders response response biomarker transcriptome sequencing transcriptomics treatment response tumor tumor growth tumor microbiota tumor microenvironment

Adverse effects Antibiotic Resistance Antibiotic Therapy Antibiotics Antibodies Antigenic Specificity Autoimmune Diseases Bacteria Bacteroides Biopsy CTLA4 gene Cancer Model Cancer Patient Cannulations Cell Wall Cells Chemosensitization Clinical Research Communities Complement Consensus Cytotoxic T-Lymphocytes Diet Disease remission Distal Event Feces Genes Genetic Diseases Genetic Engineering Gnotobiotic Growth Histologic Human IRF3 gene Immune Immune Targeting Immune response Immune system Immunotherapy Implant Individual Intestines Lead Libraries Life Lipid A Lung Adenocarcinoma Lung Neoplasms Lymph Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Mediating Metagenomics Microbe Microscopic Mismatch Repair Modeling Molecular Mimicry Molecular Target Mus Mutation Myeloid Cells Normal tissue morphology Organism PD-1/PD-L1 Patients Pattern recognition receptor Peptides Plasma Polysaccharides Population Predisposition Proteins Proteomics Relapse Research Role Serum Signal Pathway Signal Transduction Solid Solid Neoplasm Specimen Stains T-Lymphocyte T-cell receptor repertoire Testing Therapeutic Tissues Toxic effect Treatment Efficacy Tumor Immunity Tumor Tissue Wild Type Mouse Work adaptive immunity anti-PD-1 anti-PD1 therapy anti-tumor immune response antitumor effect autoimmune pathogenesis autoimmune toxicity cell killing cellular targeting checkpoint therapy cohort commensal bacteria commensal microbes design experience fecal transplantation gut microbiome gut microbiota immune checkpoint blockade immunogenic immunogenicity improved in vitro testing insight lung cancer cell mesenteric lymph node mesenteric lymphatics metabolomics microbial microbiome microbiota microorganism antigen mouse model neoantigens neoplastic cell pre-clinical programmed cell death ligand 1 rational design reconstitution responders and non-responders response response biomarker transcriptome sequencing transcriptomics treatment response tumor tumor growth tumor microbiota tumor microenvironment

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项目摘要

The discovery that the host immune system can be harnessed to attack solid tumors and improve overall survival for patients has been transformative. However, only certain tumors are responsive to immune checkpoint blockade, and an unpredictable fraction maintain durable remissions. In addition, similarly unpredictable toxicity can manifest with diverse autoimmune attack of normal tissue. Beyond PD-L1 staining and mutational burden, we have limited biomarkers of response, and we have no predictors of autoimmune toxicities. Recent studies have highlighted the contribution of the intestinal microbiota to successful PD-1/PD- L1 and CTLA-4 antibody blockade. There is, however, no consensus as to which microbes promote effective anti-tumor immune responses, and we lack an understanding of the mechanisms involved. In our proposed studies, we will seek to identify human gut-associated bacterial species and products that enhance control of lung adenocarcinoma growth following anti-PD-1 immunotherapy. We will then characterize the host cellular and molecular targets of the bacteria and their products. In preliminary studies, we identified a strain of Bacteroides vulgatus that promotes autoimmune disease and also restricts growth of implanted lung cancer cells in anti-PD-1-treated mice. This tumor model will be used to assess the immune-potentiating roles of B. vulgatus genes, such as those involved in synthesis of capsular polysaccharides and Lipid A, and to screen bacterial libraries prepared from patient super-responders, to identify species and consortia that are most effective at supporting inhibition of tumor growth. We have also developed an autochthonous lung cancer model in which neoantigens accumulate due to targeting of the mismatch repair machinery, and we will assess the ability of the candidate microbes to function in a therapeutic mode, after growth of the spontaneous tumors is established. We will then characterize differences in metabolites and proteins within lymph draining the intestine of mice colonized with immunotherapy-potentiating or control microbes, and candidate molecules will be evaluated for their activity in the tumor models. Lastly, we will seek to identify the innate signaling pathways and the relevant host target cells that convey microbial signals to the tumor microenvironment, thus enhancing immune control of tumor growth following anti-PD-1 administration. Since tumor cell killing is mediated by cytotoxic T cells, we will also determine if there are shared antigenic specificities between tumors and the microbiota. These studies will be complemented by spatial transcriptomic analyses of tumor microenvironments from mice with and without immunotherapy-potentiating microbiota. Serum from responder and non-responder lung cancer patients will be evaluated for the presence of microbiome-dependent products identified in the mouse model and tumor tissue specimens will be subjected to spatial transcriptomics analysis to determine if there are features shared with tumors in mice. Together, these studies can provide insights for designing rational strategies to utilize microbiota for potentiation of immune checkpoint blockade in cancer.

可以利用宿主免疫系统来攻击实体瘤并改善整体的发现患者的存活率是变化的。但是，只有某些肿瘤对免疫有反应检查点封锁，不可预测的部分保持了持久的恢复。另外，同样不可预测的毒性可以表现出正常组织的自身免疫性攻击。超越PD-L1染色和突变负担，我们的反应生物标志物有限，我们没有自身免疫性的预测指标毒性。最近的研究强调了肠菌对成功的PD-1/PD-的贡献 L1和CTLA-4抗体阻断。但是，对于哪种微生物促进有效的有效性尚无共识抗肿瘤的免疫反应，我们对所涉及的机制缺乏理解。在我们的建议中研究，我们将寻求确定与人类肠道相关的细菌物种和产品，以增强对抗PD-1免疫疗法后的肺腺癌生长。然后，我们将表征宿主蜂窝细菌及其产物的分子靶标。在初步研究中，我们确定了促进自身免疫性疾病并限制植入肺癌的生长的杆菌Vulgatus 抗PD-1处理的小鼠中的细胞。该肿瘤模型将用于评估B。 Vulgatus基因，例如参与胶囊多糖和脂质A的合成的基因，并进行筛选由患者超级反应者制备的细菌图书馆，以识别最多的物种和财团有效支持抑制肿瘤生长。我们还开发了一种自我肺癌新抗原因靶向不匹配维修机制而积累的新抗原的模型，我们将评估自发性肿瘤生长后，候选微生物在治疗模式下起作用的能力建立。然后，我们将表征淋巴液中代谢物和蛋白质的差异用免疫疗法抑制或对照微生物定居的小鼠肠和候选分子将评估其在肿瘤模型中的活性。最后，我们将寻求确定先天的信号通路以及将微生物信号传达给肿瘤微环境的相关宿主靶细胞，从而增强抗PD-1给药后肿瘤生长的免疫控制。由于肿瘤细胞杀戮是由细胞毒性T细胞，我们还将确定肿瘤和微生物群。这些研究将通过肿瘤的空间转录组分析来补充来自有或没有免疫疗法的微生物群的小鼠的微环境。响应者的血清将评估无反应的肺癌患者的存在微生物组依赖性产物在小鼠模型和肿瘤组织标本中鉴定出的将进行空间转录组学分析确定小鼠中是否有与肿瘤共享的特征。这些研究一起可以为设计理性策略以利用微生物群来增强癌症的免疫检查点阻滞。