Elucidating the role of intratumoral microbiota on immunotherapy efficacy

阐明肿瘤内微生物群对免疫治疗疗效的作用

• 批准号: 10449202
• 负责人: William L Redmond
• 金额: $ 19.13万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449202
• 关键词: Address; Affect; Bacteria; Bifidobacterium; Cell Communication; Cell physiology; Cells; Clinical; Communities; Data; Distant; Exposure to; Gastrointestinal tract structure; Goals; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; Immune; Immune system; Immunity; Immunotherapy; Intestinal permeability; Intestines; Knowledge; Lead; Link; Malignant Neoplasms; Metabolic; Microbe; Modeling; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oral; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Play; Primary Neoplasm; Primary carcinoma of the liver cells; Regimen; Renal Cell Carcinoma; Resistance; Role; Sampling; T-Lymphocyte; Testing; Therapeutic Intervention; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; base; body system; cancer cell; density; experimental study; fecal microbiota; gut microbiota; improved; innovation; lymph nodes; member; microbial; microbial community; microbial composition; microbial signature; microbiome; microbiota; microorganism interaction; neoplasm immunotherapy; novel; novel therapeutics; objective response rate; oral microbial community; predicting response; response; standard of care; subcutaneous; treatment response; tumor; tumor microbiota; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Microbes live in primary tumors across organ systems and in tumor metastases, making the microbes an intrinsic and essential component of the tumor microenvironment, yet what types of microbes reside in tumors and how they contribute to the tumor microenvironment, T cell function, and immunotherapy response are unknown. We modeled estimated tumor bacterial burden against the known objective response rate to immunotherapy across tumor types and observed a remarkable correlation between high bacterial burden and high response rates to immunotherapy, suggesting that the community of microbes in the tumor, or tumor microbiota, plays a pivotal role in influencing the response rate to immunotherapy. Our preliminary data supports this hypothesis, showing that increased numbers of microbial species in tumor microbiota correlate with increased numbers of immune cells in the tumor and response to immunotherapy in head and neck squamous cell carcinoma patients. However, the microbial composition of and the mechanisms by which intratumoral microbiota influence these clinical outcomes are currently unknown. While intratumoral microbiota communities remain a mystery, recent studies have implicated the influence of intestinal microbiota on immunotherapy outcome, whereby responding patients harbor specific intestinal microbial communities associated with enhanced systemic immunity and intratumoral immune infiltration. Interestingly, microbes from the gastrointestinal tract traffic to distant tumors, thus potentially seeding the intratumoral microbiota. For example, Bifidobacteria, a bacterial genera associated with immunotherapy efficacy, is known to translocate from the intestine to distant tumors. Thus, intestinal microbiota may influence immunotherapy response through microbial dissemination to tumors. Herein we propose to test whether intestinal microbes associated with immunotherapy efficacy promote bacterial or bacterial product translocation from the intestine to the lymph nodes and/or tumor. Further, we aim to uncover unique mechanisms by which intratumoral microbiota, through either direct immune cell interaction or the modulation of tumor microenvironment, influence immunotherapy efficacy. This knowledge may uncover unique opportunities to develop new therapeutic options for patients with cancer, either before standard of care treatments or synergistically through augmentation of current immunotherapy regimens. Toward this end, we hope to leverage the knowledge we gain from this proposal with respect to intratumoral microbiota to develop bacterial drugs in the localized, intratumoral setting thus minimizing systemic effects of potentially detrimental disruptions to intestinal microbial communities. Thus, our mechanistic approach has the potential to lead to innovative microbiome-based treatments that may increase the number of patients responding to immunotherapy.

项目总结/摘要 微生物生活在器官系统中的原发性肿瘤和肿瘤转移中，使微生物成为肿瘤的内在致病因子。 和肿瘤微环境的重要组成部分，但什么类型的微生物存在于肿瘤中，以及如何 它们对肿瘤微环境、T细胞功能和免疫治疗反应的贡献是未知的。我们 模型化的估计肿瘤细菌负荷与免疫治疗的已知客观缓解率 肿瘤类型，并观察到高细菌负荷和高反应率之间的显着相关性， 免疫疗法表明肿瘤中的微生物群落或肿瘤微生物群发挥着关键作用 在影响免疫治疗应答率方面的作用。我们的初步数据支持这一假设，显示 肿瘤微生物群中微生物种类数量的增加与免疫细胞数量的增加有关， 头颈部鳞状细胞癌患者肿瘤中的细胞和对免疫治疗的反应。然而，在这方面， 肿瘤内微生物群的微生物组成和机制影响这些临床 结果目前尚不清楚。虽然肿瘤内微生物群仍然是一个谜，但最近的研究表明， 已经暗示了肠道微生物群对免疫治疗结果的影响， 具有与增强的全身免疫和肿瘤内免疫相关的特定肠道微生物群落 免疫浸润有趣的是，来自胃肠道的微生物会传播到远处的肿瘤，因此可能 接种肿瘤内的微生物群。例如，双歧杆菌，一种与大肠杆菌相关的细菌属， 已知免疫治疗功效的靶向药物从肠易位到远处肿瘤。因此，肠道微生物 可能通过微生物向肿瘤的传播影响免疫治疗反应。在此，我们建议测试 与免疫治疗功效相关的肠道微生物是否促进细菌或细菌 产物从肠转移到淋巴结和/或肿瘤。此外，我们的目标是揭示 肿瘤内微生物群的独特机制，通过直接的免疫细胞相互作用或 肿瘤微环境的调节，影响免疫治疗的疗效。这些知识并 发现独特的机会，为癌症患者开发新的治疗选择，无论是在标准治疗之前， 护理治疗或协同通过增强目前的免疫治疗方案。为此目的， 我们希望利用我们从这项提案中获得的关于肿瘤内微生物群的知识， 细菌药物在局部，肿瘤内设置，从而最大限度地减少潜在有害的全身效应 破坏肠道微生物群落。因此，我们的机械方法有可能导致 创新的基于微生物组的治疗方法，可能会增加对 免疫疗法。