Elucidating the role of intratumoral microbiota on immunotherapy efficacy

项目摘要/摘要 微生物生活在原发肿瘤中，跨越器官系统，并在肿瘤转移中生活，使微生物成为固有的 以及肿瘤微环境的重要组成部分，但肿瘤中存在哪些类型的微生物以及如何 它们对肿瘤微环境、T细胞功能和免疫治疗反应的影响尚不清楚。我们 根据免疫治疗的已知客观应答率对估计的肿瘤细菌负荷进行建模 肿瘤类型，观察到高细菌负荷和高应答率之间的显著相关性 免疫疗法，表明肿瘤中的微生物群落或肿瘤微生物区系起着关键作用 在影响免疫治疗应答率中的作用。我们的初步数据支持这一假设，表明 肿瘤微生物区系中微生物种类的增加与免疫数量的增加相关 头颈部鳞状细胞癌患者肿瘤细胞与免疫治疗反应的关系然而， 肿瘤内微生物区系的微生物组成及其影响临床的机制 结果目前还不得而知。虽然肿瘤内微生物群落仍然是一个谜，但最近的研究 已暗示肠道微生物区系对免疫治疗结果的影响，从而使有反应的患者 港口特定肠道微生物群落与增强的系统免疫和肿瘤内相关 免疫渗透。有趣的是，来自胃肠道的微生物运输到远处的肿瘤，因此有可能 种植肿瘤内的微生物区系。例如，双歧杆菌，一种与 免疫治疗的疗效，已知从肠道转移到远处的肿瘤。因此，肠道微生物区系 可能通过微生物向肿瘤扩散来影响免疫治疗反应。在此，我们建议测试 与免疫治疗疗效相关的肠道微生物是促进细菌还是细菌 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 独特的机制，瘤内微生物区系，通过直接免疫细胞相互作用或 肿瘤微环境的调节，影响免疫治疗的效果。这一知识可能 发现独特的机会，为癌症患者开发新的治疗方案，无论是在标准 或通过加强目前的免疫治疗方案协同作用。为此， 我们希望利用我们从这项提议中获得的关于肿瘤内微生物区系的知识来开发 局部、肿瘤内环境中的细菌药物，从而将潜在有害的全身影响降至最低 对肠道微生物群落的破坏。因此，我们的机械论方法有可能导致 基于微生物组的创新疗法，可能会增加对 免疫疗法。

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.