TOWARDS PRECISION IMMUNO-ONCOLOGY: UNRAVELING THE GENOMIC DETERMINANTS AND MECHANISMS UNDERLYING IMMUNOTHERAPY EFFICACY AND RESISTANCE

The SARS-CoV2 virus has caused a worldwide pandemic resulting in a great deal of morbidity and many deaths. Infection with this virus causes the COVID-19 disease, which can result in acute respiratory distress syndrome. Even in patients that survive the disease, the virus can cause significant morbidity, require ventilator support for respiratory functions, and necessitate a prolonged recovery process. Interestingly, severe sequelae of COVID-19 is not uniformly distributed across the population. While some people are asymptomatic or have mild symptoms, others can rapidly succumb to the disease. Some early data have been generated that shows that cancer patients may be particularly harmed by SARS-CoV2 infection 7,8. However, the differential effects of the infection on patients with different cancers and how genetic factors influence outcomes is unknown. The overall goal of the work proposed in this supplement is to characterize the effects of critical genetic variables on COVID-19 prognosis in cancer patients. The central hypothesis of this proposal is that specific genetic features - HLA genotype and distinct somatic mutations - can strongly influence the severity of COVID19 infection. We will pursue 2 specific aims. In Aim 1, we will elucidate the effects of HLA diversity on prognosis and severity of COVID19 infection in cancer patients. Based on our preliminary data, the working hypothesis here is that HLA molecular diversity will affect prognosis in COVID19 patients with advanced cancers. We have previously developed a highly versatile method to quantitate HLA diversity called HLA evolutionary diversity (HED). We will characterize the effects of HED and HLA allelic effects on COVID severity in cancer patients. In Aim 2, we will characterize the effects of immunologically active driver mutations in cancer patients with common tumors. It is well known that certain driver genes can affect both the tumor immune environment as well as systemic immunity commonly through cytokine dysregulation. Our hypothesis here is that immunologically active cancer drivers may affect COVID19 clinical course. Using our large cohorts of cancer patients with clinical sequencing available, we will examine the effects of common somatic driver mutations on COVID19 prognosis. The combination of our aims will provide novel and impactful insights into the effects of genetic determinants on the clinical course of cancer patients who contract COVID19