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

项目总结 头颈部鳞状细胞癌(HNSCC)仍然是一种致命的疾病，尽管人们共同努力 提高其诊断和治疗水平。尽管吸烟、饮酒和HPV感染与 HNSCC，新的证据也表明，人类微生物群的变化与 HNSCC。然而，关于改变的微生物区系如何影响HNSCC的发病机制或其 治疗。目前，大多数将微生物组与癌症联系起来的研究都集中在肠道微生物区系上，这是 要么局部参与结直肠癌的发病，要么更广泛地调节新陈代谢和 系统的豁免权。口腔，这与当地的微环境有更直接的关系 HNSCC拥有人类所有解剖亚群中最复杂和最多样化的微生物群之一。 然而，肠道或口腔微生物如何塑造HNSCC的局部和系统微环境 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在体内的功能作用(S)和作用机制 并将这些发现转化为新的预防和治疗策略。我们的中央 假设在HNSCC发病过程中出现的生物失调是通过Toll样受体2信号来起作用的 针对PI3激酶的治疗加速肿瘤发展和妥协反应的途径 途径，HNSCC的关键驱动因素。这一假设是在各种出版物的基础上提出的 申请者实验室产生的初步数据，并将通过追求以下两个具体目标进行测试 将：1)验证TLR2信号介导微生物组相关的HNSCC发病机制的假设；2) 测试生物失调刺激的TLR2信号会影响抗PI3K治疗的假设。我们的方法是 创新，因为它代表了对现状的改变，利用了独特的实验鼠标 模型和最先进的技术超越了观察性的人体研究来描绘分子， 微生物群在HNSCC发病机制中的细胞、免疫机制。建议数 这项研究意义重大，因为它有望促进和扩大对微生物群如何作为 在HNSCC的发育和发展过程中，整体以及特定的微生物物种影响宿主免疫 免疫疗法。最终，这种知识有可能被开发成有效的治疗方法。 HNSCC患者，迫切需要给予本病显著的发病率和较差的预后。

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.