Germline Determinants of the Breast Cancer Immune Microenvironment

项目总结/摘要 开发有效的疗法来干扰肿瘤免疫逃避过程是进一步的挑战。 肿瘤-宿主免疫相互作用的个体间变异性使其复杂化。全基因组关联 研究（GWAS）有助于理解疾病风险背景下的个体间差异; 然而，由于缺乏表征肿瘤免疫表型的大型数据库， 我们对肿瘤-宿主免疫相互作用动力学的了解。卡特实验室最近 证明了基因型在主要组织相容性复合体（MHC）中的作用， 存在体细胞突变（Marty et al. 2017，Marty et al. 2018）。发现MHC基因型影响 致癌突变概率;由个体遗传的MHC有效呈现的驱动突变，以及 因此，受免疫监视，不太可能被观察到比驱动突变，不结合 MHC。常见的单核苷酸多态性（SNP）rs351855已知是预后不良的标志， 几种癌症产生了一种新的STAT 3结合位点，抑制细胞毒性CD 8+并促进 乳腺癌和肺癌小鼠模型中免疫抑制性CD 4 + FoxP 3 + CD 25+调节性T细胞浸润 （Kogan等人，2013）。这些发表的研究结果定义了生殖系变异在形成肿瘤中的关键作用 免疫微环境的研究还很少。对于这个提议，我们推理对比ER+和ER- 乳腺癌亚型，其在免疫细胞浸润、基线免疫治疗应答 率和炎症效应，可以形成新的生殖系研究的基础。我们计划使用独特的ER+ 和ER-乳腺癌免疫微环境，以鉴定和研究修饰 肿瘤免疫相互作用。针对这一假设，我已经鉴定出与免疫相关性显著相关的SNP。 表型，如 IFN-γ表达和细胞溶解活性，并具有细胞类型特异性效应。遵循这一 有希望的初步数据，我提出了两个具体的目的：1）阐明免疫协会和调节 与ER+和ER-乳腺癌差异相关的常见生殖系变异的机制和2） 整合常见和罕见生殖系单核苷酸变体（SNV）以预测肿瘤免疫表型。 这些目标将利用强大的生物信息学分析，并开发创新模型， 机制和相关的细胞背景的变体。预期成果将为以下方面提供重要见解： 免疫系统介导的肿瘤消除的基因组决定因素，并建立了未来的努力， 与癌症风险、进展和治疗反应相关的肿瘤免疫学。建议跨学科 研究将在加州大学圣地亚哥分校进行，导师是癌症基因组学专家， 免疫学和临床医学。这个建议将帮助我接受培训，成为一个成功的 独立的医生科学家和领域专家在精确肿瘤免疫学。

PROJECT SUMMARY/ABSTRACT Developing effective therapies to interfere in the tumor immune evasion process is a challenge further complicated by interindividual variability in tumor-host immunological interactions. Genome-wide association studies (GWAS) have been instrumental in understanding interindividual variability in the context of disease risk; however, due to the lack of large databases characterizing tumor immune phenotypes, there is a still a gap in our knowledge of the dynamics of tumor-host immune interactions. The Carter laboratory has recently demonstrated the role of genotype at the major histocompatibility complex (MHC) in shaping the landscape of presented somatic mutations (Marty et al. 2017, Marty et al. 2018). MHC genotypes were found to influence oncogenic mutation probabilities; driver mutations effectively presented by an individual’s inherited MHC, and thus subject to immunosurveillance, were less likely to be observed than driver mutations that did not bind the MHC. The common single nucleotide polymorphism (SNP) rs351855 known to be a marker of poor prognosis in several cancers generated a novel binding site for STAT3, suppressing cytotoxic CD8+ and promoting immunosuppressive CD4+FoxP3+CD25+ regulatory T cell infiltration in breast and lung cancer murine models (Kogan et al. 2013). These published findings define a critical role for germline variation in shaping the tumor immune microenvironment that is still poorly explored. For this proposal, we reasoned contrasting ER+ and ER- breast cancer subtypes, which have differences in immune cell infiltration, baseline immunotherapy response rates, and inflammatory effects, could form the basis for novel germline studies. We plan to use the distinct ER+ and ER- breast cancer immune microenvironments to identify and investigate germline variants that modify tumor-immune interactions. Towards this hypothesis, I have identified SNPs significantly associated with immune phenotypes, such as IFN-¡ expression and cytolytic activity, and with cell-type specific effects. Guided by this promising preliminary data, I propose two Specific Aims to 1) elucidate immune associations and regulatory mechanisms of common germline variants differentially associated with ER+ and ER- breast cancer and 2) integrate common and rare germline single nucleotide variants (SNVs) to predict tumor-immune phenotypes. These aims will leverage powerful bioinformatic analyses and develop innovative models to disentangle mechanisms and relevant cell contexts of the variants. Expected outcomes will provide essential insights into the genomic determinants of immune system-mediated tumor elimination and set up future efforts in precision onco-immunology related to cancer risk, progression and treatment responses. The proposed interdisciplinary research will take place at UC San Diego under the guidance of mentors who are experts in cancer genomics, immunology, and clinical medicine. This proposal will help me receive the training to become a successful independent physician-scientist and domain expert in precision onco-immunology.