Towards Precision Immuno-Oncology: Unraveling the Genomic Determinants and Mechanisms Underlying Immunotherapy Efficacy and Resistance

项目摘要/摘要 标题：走向精密免疫肿瘤学：解开基因组决定因素和机制 潜在的免疫治疗效果和耐药性 免疫疗法在改善癌症患者的预后方面显示出相当大的希望。 抗CTLA4、PD-1或PD-L1抗体的患者治疗后可产生显著的反应和 在一些患者中进行持久的肿瘤控制。然而，大多数患者并没有受益，ICB治疗可能会导致 严重的副作用。因此，在该领域中，了解这些机制是至关重要的 对ICB和其他免疫疗法的潜在敏感性和抵抗力。我们研究的长期目标是 该计划旨在揭开免疫疗法敏感性和耐药性背后的分子机制 例如ICB，并致力于更好地理解如何在精确和 个性化的方式。我们建议研究肿瘤和患者遗传学/基因组学如何影响肿瘤。 免疫表型并影响免疫治疗的反应和抵抗力。在接下来的7年里， 我们的努力将集中在解决三个重要问题上，明确的机制和翻译 关联性。首先，我们将全面分析变异景观的多样性是如何 密度和DNA损伤修复(DDR)缺陷影响接受治疗的癌症患者的免疫治疗反应 ICB(抗PD1或抗CTLA4)。这是为了开发和认证ICB的精确模型 敏感性和抵抗力，以允许设计合理的治疗组合和ICB的个性化 治疗。其次，我们将使用临床前模型和患者样本来评估驱动程序突变是如何在 关键的DDR突变影响肿瘤免疫、ICB反应和获得性耐药性。第三，我们将 描述患者生殖系基因(人类白细胞抗原)以及肿瘤的体细胞突变特征， 影响对ICB的反应。

PROJECT SUMMARY/ABSTRACT Title: Towards Precision Immuno-Oncology: Unraveling the Genomic Determinants and Mechanisms Underlying Immunotherapy Efficacy and Resistance Immunotherapy has shown considerable promise for improving outcomes for cancer patients. Treatment of patients with antibodies against CTLA4, PD-1, or PD-L1 can result in dramatic responses and durable tumor control in some patients. However, most patients do not benefit and ICB treatment can cause severe side effects. Therefore, it is of paramount importance in the field to understand the mechanisms underlying sensitivity and resistance to ICB and other immunotherapies. The long-term goal of our research program is to unravel the molecular mechanisms underlying sensitivity and resistance to immunotherapies such as ICB and to work towards a better understanding of how to use immunotherapy in a precise and individualized manner. We propose to investigate how tumor and patient genetics/genomics affect tumor immune phenotypes and influence the response and resistance to immunotherapies. Over the next 7 years, our efforts will be focused on addressing three important questions with clear mechanistic and translational relevance. First, we will undertake a comprehensive analysis of how the diversity of mutational landscapes and densities, and DNA damage repair (DDR) deficiencies affect immunotherapy response in cancers treated with ICB (anti-PD1 or anti-CTLA4). This is aimed at developing and credentialing a precise model for ICB sensitivity and resistance to allow the design of rationale therapeutic combinations and personalization of ICB treatment. Second, we will use pre-clinical models and patient samples to evaluate how driver mutations in critical DDR mutations influence tumor immunity, ICB response, and acquired resistance. Third, we will characterize how the patient germline genotype (HLA), together with somatic mutation profiles of tumors, influence response to ICB.