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.

项目摘要/摘要 微生物生活在器官系统和肿瘤转移中的原发性肿瘤中，使微生物成为固有的 肿瘤微环境的重要组成部分，然而，哪种类型的微生物位于肿瘤中 它们有助于肿瘤微环境，T细胞功能和免疫疗法反应。我们 模拟了估计的肿瘤细菌负担，以针对已知的对免疫疗法的已知客观反应率跨越 肿瘤类型，观察到高细菌负担与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社区或肿瘤微生物群具有关键性 在影响免疫疗法的反应率方面的作用。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物种数量增加与免疫数量增加 肿瘤中的细胞和对头颈鳞状细胞癌患者的免疫疗法的反应。然而， 肿瘤内微生物群会影响这些临床的微生物组成和机制 结果目前未知。虽然肿瘤内微生物群群落仍然是一个谜，但最近的研究 已经暗示了肠道菌群对免疫疗法结果的影响，从而反应患者 港口特定的肠道微生物群落与增强的全身免疫和肿瘤内相关 免疫浸润。有趣的是，从胃肠道流量到远处肿瘤的微生物，因此可能 播种肿瘤内微生物群。例如，双歧杆菌，一种与 已知免疫疗法功效，可从肠道转移到远处的肿瘤。因此，肠道菌群 通过微生物传播对肿瘤的反应可能会影响免疫疗法的反应。在此我们建议测试 与免疫疗法功效相关的肠道微生物是否促进细菌或细菌 产物从肠道转移到淋巴结和/或肿瘤。此外，我们的目标是发现 通过直接免疫细胞相互作用或 肿瘤微环境的调节，影响免疫疗法的功效。这些知识可能 在标准之前发现了为癌症患者开发新的治疗选择的独特机会 通过增加当前免疫疗法方案的增强护理治疗或协同处理。朝着这一目标， 我们希望利用我们对肿瘤内微生物群中获得的知识来发展 局部，肿瘤内环境中的细菌药物，从而最大程度地减少了潜在有害的全身效应 肠道微生物群落的破坏。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可能会增加对患者的反应 免疫疗法。