Oral Microbiota and Toll-Like Receptor Pathways in Head and Neck Cancer

项目摘要 头颈部鳞状细胞癌（HNSCC）仍然是一种致命的疾病，尽管各方共同努力， 提高其诊断和治疗水平。虽然吸烟，饮酒和HPV感染密切相关 新出现的证据也表明，人类微生物组的变化与HNSCC有关。 HNSCC。然而，关于改变的微生物群如何影响HNSCC发病机制或其 治疗目前，大多数将微生物群与癌症联系起来的研究都集中在肠道微生物群上， 或者局部促进结直肠癌发病机制，或者更广泛地调节代谢， 免疫系统。口腔，这是更直接地关系到当地的微环境， HNSCC是所有人类解剖学亚部位中最复杂和最多样化的微生物组之一。 然而，肠道或口腔微生物群如何塑造HNSCC中的局部和全身微环境， 发病机制和治疗方法完全未知。 我们的长期目标是确定微生物组的功能作用和作用机制， HNSCC并将这些发现转化为新的预防和治疗策略。我们的中央 假设HNSCC发病过程中出现的生态失调通过Toll样受体2信号传导起作用 加速肿瘤发展和损害对PI3激酶治疗反应的途径 途径，HNSCC的关键驱动因素。这一假设是根据出版物提出的， 申请者实验室产生的初步数据，并将通过两个具体目标进行测试， 将：1）检验TLR2信号传导介导微生物组相关HNSCC发病机制的假设，以及2） 检验生态失调刺激的TLR2信号传导损害抗PI3K治疗的假设。我们的做法是 创新，因为它通过利用独特的实验小鼠， 模型和最先进的技术，超越观察性人类研究，描绘分子， HNSCC发病机制中微生物组诱导的细胞和免疫机制。拟议 这项研究意义重大，因为它有望促进和扩大对微生物组如何作为 整体以及特定的微生物物种影响HNSCC发展中的宿主免疫力， 免疫疗法最终，这些知识有可能被开发成有效的治疗方法， HNSCC患者，迫切需要考虑到这种疾病的显著发病率和不良预后。

PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC) remains a lethal disease despite concerted efforts to improve its diagnosis and treatment. Although smoking, drinking, and HPV infection are closely linked to HNSCC, emerging evidence also suggests that changes in the human microbiome are associated with HNSCC. However, little is known about how the altered microbiota affect HNSCC pathogenesis or its treatment. Currently, most studies linking the microbiome to cancer have focused on gut microbiota, which either contributes locally to colorectal cancer pathogenesis, or more broadly, modulates metabolism and immunity systemically. The oral cavity, which is more directly relevant to the local microenvironment in HNSCC, harbors one of the most complex and diverse microbiomes of all human anatomical sub-sites. However, how either the gut or oral microbiotas shape the local and systemic microenvironment in HNSCC pathogenesis and treatment are completely unknown. Our long-term goal is to determine the functional role(s) and mechanisms of action of the microbiome in HNSCC and to translate these findings into novel preventative and therapeutic strategies. Our central hypothesis is that dysbiosis arising during HNSCC pathogenesis acts through Toll-like Receptor 2 signaling pathways to accelerate tumor development and compromise response to therapies directed at the PI3 kinase pathway, a key driver of HNSCC. This hypothesis has been formulated on the basis of publications and preliminary data produced in the applicants' laboratories and will be tested by pursuing two specific aims that will: 1) Test the hypothesis that TLR2 signaling mediates microbiome-related HNSCC pathogenesis and 2) Test the hypothesis that dysbiosis-stimulated TLR2 signaling compromises anti-PI3K therapy. Our approach is innovative because it represents a departure from the status quo by utilizing unique experimental mouse models and state-of-art technologies to move beyond observational human studies to delineate the molecular, cellular, and immunological mechanisms induced by the microbiome in HNSCC pathogenesis. The proposed research is significant because it is expected to advance and expand understanding of how the microbiome as a whole, as well as specific microbial species, impacts host immunity in HNSCC development and immunotherapy. Ultimately, such knowledge has the potential to be developed into effective therapies for HNSCC patients, a pressing need given the significant incidence and poor prognosis of this disease.