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

SARS-CoV2病毒已经引起了一场全球性的大流行，导致了大量的发病率和许多人的死亡。感染这种病毒会导致新冠肺炎病，这可能会导致急性呼吸窘迫综合征。即使在疾病中幸存下来的患者，病毒也可能导致显著的发病率，需要呼吸机支持呼吸功能，并需要长期的康复过程。有趣的是，新冠肺炎的严重后遗症并没有在人群中均匀分布。虽然有些人没有症状或症状轻微，但另一些人可能很快就会死于这种疾病。一些早期数据显示，癌症患者可能会受到SARS-CoV2感染的特别伤害，7，8。然而，这种感染对不同癌症患者的不同影响以及遗传因素如何影响预后尚不清楚。本附录中提出的工作的总体目标是表征关键遗传变量对癌症患者新冠肺炎预后的影响。这一建议的中心假设是，特定的遗传特征--人类白细胞抗原基因和独特的体细胞突变--可以强烈地影响COVID19感染的严重程度。我们将追求两个具体目标。在目标1中，我们将阐明人类白细胞抗原的多样性对癌症患者预后和COVID19感染严重程度的影响。根据我们的初步数据，这里的工作假设是，人类白细胞抗原分子多样性将影响COVID19晚期癌症患者的预后。我们之前已经开发了一种高度通用的方法来量化人类白细胞抗原多样性，称为人类白细胞抗原进化多样性(HED)。我们将描述HED和HLA等位基因效应对癌症患者COVID严重程度的影响。在目标2中，我们将描述免疫活性驱动基因突变在患有常见肿瘤的癌症患者中的作用。众所周知，某些驱动基因可以影响肿瘤免疫环境和系统免疫，通常是通过细胞因子失调来实现的。我们的假设是，免疫活跃的癌症驱动因素可能会影响COVID19的临床进程。利用我们拥有临床测序的大量癌症患者队列，我们将检查常见的体细胞驱动基因突变对COVID19预后的影响。我们的目标的结合将为基因决定因素对感染COVID19的癌症患者临床病程的影响提供新的和有影响力的见解

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 infection7,8. 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