Immune Regulation of COVID-19 Infection in Cancer and Autoimmunity

1摘要 SARS-CoV-2在世界范围内的负面影响在许多不同方面都是天文数字，影响到所有人 社会的三个方面。到目前为止，已有1300多万人感染，60多万人死亡 4个占比。目前对病毒调节免疫反应的认识不足是一种 5缺乏可改善病毒的有效预防和治疗方法的主导因素 6传播和死亡率。新冠肺炎病在发病率和临床病程上具有很大的异质性，由于 7民族背景、年龄及既往临床情况。严重的柯萨奇病毒19和增加的死亡率 据报道，在癌症患者和非裔美国人(AA)中发现了8例。这些产品中有一个共同特点 9个群体是基础炎症水平的升高，可以与SARS-COV-2驱动的 10炎症导致临床预后不佳。这种促炎环境会加重淋巴细胞减少症。 11已经在新冠肺炎病中流行，可能导致T细胞动态平衡紊乱，T细胞不足有帮助 12和缺乏存活的记忆T和B细胞室。当前提案的一个核心推论是 13患有潜在免疫失调的人，例如癌症患者，会有异常反应 14到新冠肺炎，调解不良的短期结果和长期免疫记忆的损害。至 15直接解决这个问题，我们可以接触到强大的受试者队列，包括AA的高代表性， 16例患有肺癌和B细胞淋巴瘤。我们的策略将产生B细胞反应的精确量化 17在功能(中和、效应功能)和细胞水平(B细胞/浆母细胞的深层表型， 18 BCR序列的多样性)。最先进的检测方法包括单细胞RNAseq、CITEseq、ATACseq、HIGH 19密度流式细胞术、细胞因子阵列、循环代谢物和微生物组将提供高维 癌症患者炎性环境及其对先天功能、转铁蛋白功能的影响 21长寿B细胞和T细胞记忆反应。B细胞功能的这些测量方法(目标1)与 22从组学数据(目标2-3)产生的那些将有助于确定机制 23个在癌症背景下增强疾病严重性的基础。具体来说，我们建议： 24 1)分析SARS-CoV-2感染后抗原特异性B细胞反应的动态和持久性 癌症患者与非癌症患者之间的比较 26 2)确定普遍存在的炎症环境触发的分子和细胞机制 27新冠肺炎期间体液反应受损的急性感染中的癌症患者 28 3)确定SARS-CoV-2感染和/或触发的表观遗传和转录机制 29微生物易位将阻碍记忆B细胞和TFH细胞的寿命。 30这一集体努力旨在阐明新冠肺炎免疫干预和/或预防的更好途径。 31 32 33个叙事 34本提案旨在了解癌症患者感染SARS-COV-2的机制基础 35，导致预后恶化。我们将剖析先天免疫反应和获得性免疫反应的特点 36使用无偏见的整体方法来确定癌症宿主环境对定性和定量的影响 37保护性记忆T和B细胞反应的特征。我们的主要目标是开发新的有效的 38项干预措施，以治疗这一严重受影响的人口。 39 40岁 41

1 Abstract 2 The negative impact of SARS-CoV-2 worldwide has been astronomical in many different ways, impacting on all 3 aspects of society. Up to date more than 13 million infections and over 600,000 deaths have already been 4 accounted for. The current lack of understanding of the modulation of the immune response by the virus is a 5 dominant factor in the absence of effective prophylactic, therapeutic approaches which can ameliorate virus 6 transmission and mortality. COVID-19 disease is greatly heterogeneous in incidence and clinical course, due in 7 part to ethnic background, age and pre-existing clinical conditions. Severe COVID19 and increased death rate 8 has been reported in cancer patients and in African-Americans (AA). One common feature among these 9 populations is the heightened basal level of inflammation that could synergize with the SARS-COV-2 driven 10 inflammation leading to poor clinical outcomes. This pro-inflammatory milieu will exacerbate the lymphopenia 11 already prevalent in COVID-19 disease and which could lead to disrupted T cell homeostasis, poor T cell help 12 and lack of survival of the memory T and B cell compartments. A central corollary of the current proposal is 13 that individuals with underlying immune dysregulation, such as in cancer, will have abnormal responses 14 to COVID-19, mediating poor short-term outcomes and impairment of long term immune memory. To 15 address this directly, we have access to well-powered cohorts of subjects, including high representation of AA, 16 with lung cancer and B cell lymphomas. Our strategy will generate precise quantification of the B cell response 17 at the functional (neutralization, effector function) and cellular level (deep phenotyping of B cell/plasmablasts, 18 diversity of BCR sequences). State-of-the-art assays including single cell RNAseq, CITEseq, ATACseq, high 19 density flow cytometry, cytokine array, circulating metabolites and microbiome will provide high dimensional 20 analysis of the inflammatory milieu in cancer subjects and its impact on innate and Tfh function as well as 21 longevity of B cell and T cell memory responses. Integration of these measures of B cell function (Aim 1) with 22 those generated from the OMICs data (Aim 2-3) will contribute to the identification of the mechanistic 23 underpinnings that enhance disease severity in the context of cancer. Specifically, we propose to: 24 1) Analyze the dynamics and durability of antigen-specific B cell responses after SARS-CoV-2 infection 25 in cancer patients compared to patients without cancer 26 2) identify the molecular and cellular mechanisms triggered by the inflammatory environment prevalent 27 in cancer patients during acute infection which impairs humoral responses during COVID-19 28 3) Identify the epigenetic and transcriptional mechanisms triggered by SARS-CoV-2 infection and/or 29 microbial translocation that will impede on the longevity of memory B and Tfh cells. 30 This collective effort aims to elucidate better paths for immune intervention and/or prevention in COVID-19. 31 32 33 Narrative 34 This proposal aims at understanding the mechanistic underpinnings of SARS-COV-2 infection in cancer patients 35 which lead to their worsened prognosis. We will dissect features of the innate and adaptive immune responses 36 using unbiased holistic approaches to define the impact of the cancer host milieu on qualitative and quantitative 37 features of the protective memory T and B cell response. Our major goal is to develop novel effective 38 interventions to treat this severely affected population. 39 40 41