Racial differences in Immunogenetic Tumorigenesis of Head and Neck Squamous Cell Carcinoma

摘要 生存研究表明，非洲裔美国人(AA)在头颈部癌症中存在明显的种族差异效应 还有白人。再生障碍性贫血可能会出现更严重的疾病，年龄调整后的死亡率是前者的两倍 与白人相比。免疫检查点抑制剂为一些复发或复发的患者带来了新的希望 转移性疾病，但治疗的进一步改善取决于开发一种全面的 HNSCC肿瘤演变的免疫遗传学图谱。近20%的口腔癌患者患有多发性口腔癌 癌前病变表现为不典型增生的迹象，通常在视觉上被识别为白斑。因为其中的一些 病变演变为恶性肿瘤，代表HPV阴性口腔鳞状细胞的中间步骤 癌症(OSCC)进展。在肿瘤发展的最早阶段出现的基因变化会导致肿瘤 发展并抑制免疫系统摧毁癌前细胞的倾向。遗传异常 在口腔鳞状细胞癌进化过程中选择可以通过上调来创造功能失调的肿瘤免疫微环境 诱导免疫耐受和T细胞耗竭的关键免疫调节配体。相声的作用 在肿瘤细胞及其免疫微环境之间，特别是在其早期发育阶段， 目前尚不清楚。此外，再生障碍性贫血的这些病变中几乎没有基线信息，知道的更少。 关于导致这一群体进展和免疫入侵的关键基因变化。中环 这个项目的前提是在遗传和体细胞遗传变化过程中的关键种族差异 口腔鳞癌的进展影响肿瘤内关键免疫调节细胞因子或配体的表达 以逃避抗肿瘤免疫反应的微环境。该项目的具体目标将使用 全外显子组测序、RNA测序、高通量计算分析和组织细胞 定位方法，以绘制特定的突变模式和相应的免疫图谱 通过关键免疫调节配体的表达和免疫耐受和T细胞耗竭的信号 口腔肿瘤发生途径上的病变。这些数据将帮助我们了解 不同的进展途径和与免疫微环境的相互作用。这样的映射应该 提供对风险评估、肿瘤监测和治疗具有重大影响的重要见解 再生障碍性贫血患者口腔鳞癌的干预。

Abstract Survival studies show marked racial disparity effect in head and neck cancer between African Americans (AA) and whites. AA may present with more advanced disease and have twice the age-adjusted mortality rate compared with whites. Immune checkpoint inhibitors offer new hope for some patients with recurrent or metastatic disease, but further improvement in therapy is contingent upon developing a comprehensive immunogenetic map of neoplastic evolution in HNSCC. Nearly 20% of patients with oral cancers harbor multiple pre-malignant lesions showing signs of dysplasia, often visually identified as leukoplakia. As some of these lesions evolve to malignant neoplasms, they represent intermediate steps in HPV negative oral squamous cell carcinoma (OSCC) progression. Genetic changes arising at the earliest stages of tumor development drive tumor progression and curtail the propensity of the immune system to destroy precancerous cells. Genetic aberrations selected during OSCC evolution can create a dysfunctional tumor immune microenvironment by upregulating key immunomodulatory ligands that induce immune tolerance and T cell exhaustion. The role of cross-talk between neoplastic cells and their immune microenvironment, particularly in its early developmental stages, has yet to be elucidated. Moreover, little baseline information exists in these lesions in AA, and even less is known about the key genetic changes that lead to progression and immune invasion in this population. The central premise of this project is that key racial differences in both inherited and somatic genetic changes during the progression of OSCC impact the expression of key immunomodulatory cytokines or ligands within the tumor microenvironment in order to escape an antitumor immune response. The specific aims of this project will use whole-exome sequencing, RNA sequencing, high-throughput computational analyses, and tissue cell localization methods to map the specific mutational patterns and corresponding immune landscape represented by expression of key immunomodulatory ligands and signatures of immune tolerance and T cell exhaustion in lesions along the pathway of oral tumorigenesis. This data will help us understand the biologic underpinnings of the different progression pathways and interactions with the immune microenvironment. Such mapping should provide crucial insights that have significant implications for risk assessment, tumor surveillance and treatment interventions for OSCC in AA patients.