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: 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
• 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

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以被利用来攻击实体瘤并改善整体 患者的生存率已经发生了变化。然而，只有某些肿瘤对免疫应答有反应， 检查站封锁和不可预测的部分维持持久的缓解。此外，同样 不可预测的毒性可表现为正常组织的多种自身免疫攻击。除PD-L1染色外 和突变负担，我们有有限的生物标志物的反应，我们没有预测自身免疫性疾病， 毒性最近的研究强调了肠道微生物群对成功的PD-1/PD-1的贡献。 L1和CTLA-4抗体阻断。然而，对于哪些微生物促进有效的 抗肿瘤免疫反应，我们缺乏对相关机制的了解。在我们提出的 研究，我们将寻求确定人类肠道相关的细菌物种和产品，以加强控制 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 以及细菌及其产物的分子靶点。在初步研究中，我们发现了一种 促进自身免疫性疾病并限制植入性肺癌生长的普通拟杆菌 抗PD-1处理的小鼠中的细胞。该肿瘤模型将用于评估B的免疫增强作用。 vulgatus基因，如参与荚膜多糖和脂质A合成的那些，并筛选 从患者超级应答者制备的细菌文库，以鉴定最常见的物种和聚生体， 有效支持肿瘤生长的抑制。我们还发现了一种原发性肺癌 模型中，由于靶向错配修复机制，新抗原积累，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 是成立的。然后，我们将描述淋巴引流内代谢物和蛋白质的差异， 在用免疫治疗增强微生物或对照微生物定殖的小鼠的肠中，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给药后肿瘤生长的免疫控制。由于肿瘤细胞的杀伤是由 细胞毒性T细胞，我们还将确定是否有共享的抗原特异性之间的肿瘤和细胞毒性T细胞， 微生物群这些研究将通过肿瘤的空间转录组学分析来补充。 图2显示了来自具有和不具有免疫治疗增强微生物群的小鼠的微环境的结果。应答者血清 将评估无反应肺癌患者是否存在微生物组依赖性产物 将对小鼠模型和肿瘤组织标本中鉴定的肿瘤细胞进行空间转录组学分析 以确定是否有与小鼠肿瘤相同的特征。总之，这些研究可以提供见解， 设计合理的策略以利用微生物群来增强癌症中的免疫检查点阻断。