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

• 批准号: 10299034
• 负责人: Dan Littman
• 金额: $ 57.22万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10299034
• 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; reconstitution; responders and non-responders; response; response biomarker; transcriptome sequencing; transcriptomics; treatment response; tumor; tumor growth; tumor microbiota; tumor microenvironment

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.

发现宿主免疫系统可被利用来攻击实体肿瘤并全面改善 患者的生存一直是变革性的。然而，只有某些肿瘤对免疫有反应。 检查站封锁，以及不可预测的一小部分人维持持久的缓解。此外，同样 不可预测的毒性可表现为对正常组织的各种自身免疫攻击。超越PD-L1染色 和突变负担，我们有有限的生物标记物的反应，我们没有预测的自身免疫 毒物。最近的研究强调了肠道微生物区系对成功的PD-1/PD-1的贡献。 L1和CTLA-4抗体阻断。然而，对于哪种微生物促进有效的作用还没有达成共识 抗肿瘤免疫反应，我们对其中涉及的机制缺乏了解。在我们提议的 研究，我们将寻求确定与人类肠道相关的细菌种类和产品，以加强对 抗PD-1免疫治疗后的肺腺癌生长。然后我们将描述宿主细胞的特征 细菌及其产物的分子靶标。在初步研究中，我们发现了一株 促进自身免疫性疾病并限制植入性肺癌生长的寻常型杆菌 抗PD-1处理的小鼠的细胞。该肿瘤模型将被用来评估B的免疫增强作用。 包膜多糖和脂类A合成相关基因的克隆和筛选 从患者超级应答者准备的细菌库，以识别最常见的物种和联合体 有效支持抑制肿瘤生长。我们还患上了一种原发肺癌 由于错配修复机制的靶向而导致新抗原积累的模型，我们将评估 候选微生物在自发性肿瘤生长后以治疗模式发挥作用的能力 已经确立了。然后我们将描述淋巴中代谢产物和蛋白质的差异。 免疫治疗的小鼠肠道--增强或控制微生物，候选分子将 在肿瘤模型中评估它们的活性。最后，我们将试图确定先天的信号通路 以及将微生物信号传递到肿瘤微环境的相关宿主靶细胞，从而增强 抗PD-1抗体对肿瘤生长的免疫控制。由于肿瘤细胞杀伤是由 细胞毒性T细胞，我们还将确定肿瘤和肿瘤之间是否存在共同的抗原特异性 微生物区系。这些研究将得到肿瘤的空间转录分析的补充。 来自免疫治疗和不免疫治疗的小鼠的微环境--增强微生物区系。来自应答者的血清 无反应的肺癌患者将接受微生物组依赖产物的评估 对鉴定出的小鼠模型和肿瘤组织标本进行空间转录分析 以确定是否存在与小鼠肿瘤相同的特征。总而言之，这些研究可以为 设计合理的策略，利用微生物区系加强癌症免疫检查点的阻断。