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

头颈鳞状细胞癌免疫遗传肿瘤发生的种族差异

• 批准号: 10667649
• 负责人: DAVID SIDRANSKY
• 金额: $ 46.42万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-18 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667649
• 关键词: Affect; African American; African American population; Age; Biological; Biological Factors; Biopsy; CD8B1 gene; CDKN2A gene; Cells; Clinical; Computer Analysis; DNA; Data; Demographic Factors; Development; Disease; Dysplasia; Early Diagnosis; Event; Evolution; FGFR1 gene; Genetic; Genomics; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Histologic; Human; Human Papillomavirus; Human papilloma virus infection; Immune; Immune System Diseases; Immune Tolerance; Immune checkpoint inhibitor; Immune response; Immune system; Immunogenetics; Immunologic Surveillance; Immunophenotyping; Inherited; Intervention; Invaded; Knowledge; Lead; Lesion; Lesion by Stage; Leucocytic infiltrate; Leukoplakia; Ligands; Link; Location; Low Prevalence; Malignant - descriptor; Malignant Neoplasms; Maps; Methods; Molecular; Mutation; Mutation Analysis; Oral Stage; Oral cavity; Outcome; PIK3CA gene; Pathway interactions; Patients; Pattern; Population; Premalignant Cell; Preneoplastic Conditions; Primary Neoplasm; Prognosis; RAS genes; RNA; Recurrence; Regulatory T-Lymphocyte; Resected; Resolution; Risk Assessment; Role; Sampling; Severe dysplasia; Shapes; Socioeconomic Status; Somatic Mutation; T-Lymphocyte; TP53 gene; The Cancer Genome Atlas; Therapeutic Intervention; Time; Tissues; Tumor stage; Visual; advanced disease; anti-tumor immune response; bioinformatics tool; cancer invasiveness; carcinogenesis; cell mediated immune response; cytokine; design; disorder risk; exhaustion; exome; exome sequencing; extracellular; health care availability; immunoregulation; improved; in vitro Model; insight; interest; malignant mouth neoplasm; mortality; mouth squamous cell carcinoma; neoplastic; neoplastic cell; oral lesion; oral tumorigenesis; outcome disparities; premalignant; prognostic; progression risk; racial difference; racial disparity; racial population; risk prediction; survival disparity; targeted treatment; therapeutic target; transcriptome sequencing; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis

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.

摘要 生存研究显示，非裔美国人（AA）之间头颈癌的种族差异效应显著 还有白人AA可能会出现更严重的疾病，并且年龄调整后的死亡率是其两倍 与白人相比。免疫检查点抑制剂为一些复发性或 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肿瘤演变免疫遗传学图谱近20%的口腔癌患者患有多种癌症 癌前病变显示发育异常的迹象，通常视觉上被识别为白斑。因为其中一些 病变演变为恶性肿瘤，它们代表HPV阴性口腔鳞状细胞癌的中间步骤， 癌（OSCC）进展。在肿瘤发展的最早阶段出现的遗传变化驱动肿瘤 发展和减少免疫系统破坏癌前细胞的倾向。遗传畸变 在OSCC演变过程中选择的一种细胞因子可以通过上调 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 肿瘤细胞与其免疫微环境之间的关系，特别是在其早期发育阶段， 尚未阐明。此外，很少有基线信息存在于这些病变在AA，甚至更少是已知的 关于导致这一人群疾病进展和免疫入侵的关键基因变化。中央 这个项目的前提是，在遗传和体细胞遗传变化的关键种族差异，在这一过程中， OSCC的进展影响肿瘤内关键免疫调节细胞因子或配体的表达 微环境，以逃避抗肿瘤免疫反应。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 定位方法来映射特定的突变模式和相应的免疫景观表示 通过表达关键的免疫调节配体和免疫耐受和T细胞耗竭的特征， 病变沿着口腔肿瘤发生的途径。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。这种映射应 提供对风险评估、肿瘤监测和治疗具有重大意义的关键见解 对AA患者的OSCC进行干预。