Oral microbiome and inflammatory status in antimicrobially-treated oral cancer patients

摘要 口腔鳞状细胞癌(OSCC)是头颈部最常见的癌症类型， 在美国众多人口群体中继续上升，但其5年存活率并未提高 几十年来。尽管靶向治疗、免疫治疗和其他新的辅助方案取得了进展， 局部晚期和复发/转移性疾病的患者继续有极差的 结果，强调需要对口腔鳞状细胞癌进行更有效的治疗，这种疾病通常直到 它已经进入了后期阶段。OSCC的主要危险因素包括吸烟、饮酒和 口咽癌、HPV感染，但癌症发病率受到其他因素的影响，如 解剖部位、患者的人口统计数据，可能还有个体的口腔微生物群。鉴于口腔鳞癌的病例是 尽管美国采取了有针对性的头颈部癌症预防措施，如戒烟和 HPV疫苗接种，有充分的理由探索其他可改变的风险因素，这些因素与新的 治疗，可以改善口腔鳞状细胞癌和其他侵袭性头颈部癌症患者的预后。 口腔微生物群是一个复杂而动态的共生生物群落，可以成为 饮食摄入、烟酒使用和糟糕的牙科卫生造成的不平衡(“生物失调”)。 生物失调可通过丰富细菌病原体而使个人预先患上口腔疾病，包括癌症。 促进致癌，分泌致癌化合物，促进慢性炎症。因此， 逆转口腔微生物失调是预防肿瘤发生的一种很有前途的方法。食品添加剂Nisin， 它对广泛的病原体具有杀菌作用，已被证明可以恢复口腔微生物群的多样性， 在体外和多菌小鼠模型中抑制炎症和刺激抗肿瘤细胞反应 治疗口腔癌，同时保持其良好的安全性。然而，Nisin的潜在临床益处 用于治疗人类口腔鳞癌的药物尚未被研究过。在此，我们建议进行一项I/IIa阶段试验，以确定 代表高危人群的口腔鳞癌患者对Nisin的耐受性和可行性。同时， 我们将进行Nisin的机理研究及其对口腔微生物群落结构的影响， 研究参与者的炎症体表达和抗癌细胞反应。我们还将分析 关键口腔细菌中Nisin耐药性的出现，这可能为规避Nisin提供洞察 在其他临床情况下的耐药性。我们推测Nisin在口腔鳞癌患者中的耐受性良好， 将通过抑制细菌病原体的生长和促进抗肿瘤环境来对抗生物失调 免疫调节和抗肿瘤细胞活性。我们的长期目标是验证Nisin是一种有前途的 口腔鳞癌治疗的候选人，并证明口腔生物失调是人类肿瘤发生的主要驱动因素 这是可以操纵的，从而突出了重要但大多未被认识到的保护作用，即 抗菌剂可以有效地对抗人类的癌症。

ABSTRACT The incidence of oral squamous cell carcinoma (OSCC), the most common type of head and neck cancer, continues to rise among numerous demographic groups in the US, yet its 5-year survival rate has not improved for several decades. Despite advances in targeted therapy, immunotherapy and other novel adjuvant regimens, patients with locoregionally advanced and recurrent/metastatic disease continue to have extremely poor outcomes, underscoring the need for more effective treatments for OSCC, which often goes undiagnosed until it has reached late stages. Primary risk factors for OSCC include tobacco use, alcohol consumption, and for oropharyngeal cancers, HPV infection, but cancer incidence is influenced by additional elements such as anatomic site, patient demographics, and likely the individual’s oral microbiome. Given that cases of OSCC are increasing despite targeted head and neck cancer prevention efforts in the US such as smoking cessation and HPV vaccination, there is a strong rationale for exploring other modifiable risk factors that, together with new therapies, can improve outcomes for patients with OSCC as well as other aggressive head and neck cancers. The oral microbiome is a complex and dynamic community of commensal organisms that can become imbalanced (“dysbiotic”) in response to dietary intake, tobacco and alcohol use, and poor dental hygiene. Dysbiosis can pre-dispose an individual to oral disease, including cancer, by enriching for bacterial pathogens that promote carcinogenesis, secrete carcinogenic compounds, and promote chronic inflammation. Thus, reversing oral dysbiosis is a promising approach for protecting against tumorigenesis. The food additive nisin, which is bactericidal against a broad range of pathogens, has been shown to restore oral microbiome diversity, suppress inflammation, and stimulate anti-tumor cellular responses in vitro and in a polymicrobial mouse model of oral cancer, while maintaining its well-established safety profile. However, the potential clinical benefit of nisin for treating OSCC in humans has not been investigated. Here, we propose a Phase I/IIa trial to establish the tolerability and feasibility of administering nisin to OSCC patients who represent high-risk populations. In parallel, we will perform mechanistic studies of nisin and its effects on oral microbiome community structure, inflammasome expression, and anti-cancer cellular responses of the study participants. We will also analyze the emergence of nisin resistance among key oral bacteria, which could provide insight into circumventing nisin resistance in other clinical contexts. We hypothesize that nisin will be well-tolerated among OSCC patients and will counter dysbiosis by inhibiting bacterial pathogen growth and promoting an anti-tumorigenic environment via immunomodulation and anti-cancer cell activity. Our long-term goals are to validate nisin as a promising candidate for OSCC treatment and demonstrate that oral dysbiosis is a major driver of tumorigenesis in humans that can be manipulated, thus highlighting the important yet mostly unrecognized protective role that antimicrobials can exert against cancer in humans.