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.