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: 10516823
• 负责人: DAVID SIDRANSKY
• 金额: $ 48.96万
• 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/10516823
• 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; Knowledge; Lead; Lesion; Lesion by Stage; Leukocytes; Leukoplakia; Ligands; Link; Location; Low Prevalence; Malignant - descriptor; Malignant Neoplasms; Maps; Mediating; 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; Race; 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; advanced disease; anti-tumor immune response; bioinformatics tool; cancer invasiveness; carcinogenesis; cytokine; design; disorder risk; exhaustion; exome; exome sequencing; extracellular; health care availability; immunoregulation; in vitro Model; insight; interest; malignant mouth neoplasm; mortality; mouth squamous cell carcinoma; neoplastic; neoplastic cell; oral lesion; oral tumorigenesis; premalignant; prognostic; racial difference; racial disparity; risk prediction; survival disparity; targeted treatment; therapeutic target; transcriptome sequencing; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis; 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; Knowledge; Lead; Lesion; Lesion by Stage; Leukocytes; Leukoplakia; Ligands; Link; Location; Low Prevalence; Malignant - descriptor; Malignant Neoplasms; Maps; Mediating; 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; Race; 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; advanced disease; anti-tumor immune response; bioinformatics tool; cancer invasiveness; carcinogenesis; cytokine; design; disorder risk; exhaustion; exome; exome sequencing; extracellular; health care availability; immunoregulation; in vitro Model; insight; interest; malignant mouth neoplasm; mortality; mouth squamous cell carcinoma; neoplastic; neoplastic cell; oral lesion; oral tumorigenesis; premalignant; prognostic; racial difference; racial disparity; 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.

抽象的 生存研究表明，非裔美国人之间的头颈癌的种族差异效应明显 和白人。 AA可能患有更晚期疾病，并具有年龄调整后的死亡率的两倍 与白人相比。免疫检查点抑制剂为某些经常性或 转移性疾病，但治疗的进一步改善取决于建立全面的 HNSCC中肿瘤进化的免疫遗传图。近20％的口服癌症患者藏有多个 恶性病变显示出发育不良的迹象，通常在视觉上被识别为白细胞。作为其中一些 病变演变为恶性肿瘤，它们代表HPV阴性口服鳞状细胞中的中间步骤 癌（OSCC）进展。在肿瘤发育最早阶段产生的遗传变化驱动肿瘤 进展和减少免疫系统破坏癌前细胞的倾向。遗传畸变 在OSCC演化期间选择可以通过上调产生功能失调的肿瘤免疫微环境 诱导免疫耐受性和T细胞耗尽的关键免疫调节配体。交叉言论的作用 在肿瘤细胞和它们的免疫微环境之间，特别是在其早期发育阶段， 尚待阐明。此外，AA中的这些病变中几乎没有基线信息，甚至更少已知 关于导致该人群进展和免疫侵袭的关键遗传变化。中央 该项目的前提是，在遗传和躯体遗传变化中的主要种族差异在 OSCC的进展会影响肿瘤中关键免疫调节细胞因子或配体的表达 微环境为了逃避抗肿瘤免疫反应。该项目的具体目标将使用 全外观测序，RNA测序，高通量计算分析和组织细胞 绘制特定突变模式和相应的免疫景观的定位方法 通过表达关键免疫调节配体以及免疫耐受性和T细胞耗尽的特征 沿着口腔肿瘤发生途径的病变。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，肿瘤监视和治疗具有重大影响的关键见解 AA患者的OSCC干预措施。