Germline Determinants of the Breast Cancer Immune Microenvironment

项目摘要/摘要 开发有效的治疗方法来干预肿瘤免疫逃避过程是一个进一步的挑战 在肿瘤-宿主免疫相互作用中，个体间的差异使其复杂化。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，在 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 证明了主要组织相容性复合体(MHC)上的基因在塑造人类免疫缺陷病毒的格局中的作用 呈现体细胞突变(Marty等人2017年，Marty等人。2018年)。MHC基因型别被发现会影响 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，受到免疫监控的基因比不结合基因的驱动突变更不可能被观察到 MHC。常见的单核苷酸多态(SNP)rs351855被认为是预后不良的标志 几种癌症产生了一个新的STAT3结合位点，抑制细胞毒CD8并促进 乳腺癌和肺癌小鼠模型中免疫抑制的CD4、FoxP3、CD25调节性T细胞的浸润 (Kogan等人)2013)。这些发表的发现明确了生殖系变异在肿瘤形成中的关键作用。 免疫微环境仍未得到很好的探索。对于这项提议，我们认为对比ER和ER- 免疫细胞浸润不同的乳腺癌亚型，基线免疫治疗反应 比率和炎症效应，可能构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，以识别和研究改变 肿瘤与免疫的相互作用。对于这一假设，我发现了与免疫显著相关的SNPs 表型，例如 干扰素-1的表达和细胞杀伤活性，并具有细胞类型特异性效应。以此为指导 有希望的初步数据，我提出了两个具体目标：1)阐明免疫关联和调节 与ER和ER不同相关的常见生殖系变异的机制-乳腺癌和2) 结合常见和罕见的生殖系单核苷酸变异(SNV)来预测肿瘤免疫表型。 这些目标将利用强大的生物信息学分析和开发创新模型来解开 变异体的机制和相关的细胞上下文。预期结果将为以下方面提供重要的见解 免疫系统介导的肿瘤清除的基因组决定因素及其未来的精确研究 肿瘤免疫学与癌症风险、进展和治疗反应有关。拟议的跨学科 这项研究将在加州大学圣地亚哥分校在癌症基因组专家的指导下进行， 免疫学和临床医学。这项建议将帮助我接受培训，成为一名成功的 独立内科医生、科学家和精确肿瘤免疫学领域的专家。

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.