Molecular Determinants and Therapeutic Consequences of Immune Heterogeneity in Cancer

癌症免疫异质性的分子决定因素和治疗后果

• 批准号: 10001329
• 负责人: BEN Z STANGER
• 金额: $ 82.01万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001329
• 关键词: Antitumor Response; Attention; Biology; Clinical; Environment; Epigenetic Process; Event; Exhibits; Fostering; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Heterogeneity; Human; Immune; Immune response; Immunotherapy; Inter-tumoral heterogeneity; Intrinsic factor; Malignant Neoplasms; Modeling; Molds; Molecular; Molecular Abnormality; Mus; Myeloid Cells; Myofibroblast; Pancreatic Ductal Adenocarcinoma; Population; SHH gene; Sampling; Shapes; Source; Study models; T-Lymphocyte; Therapeutic; Tumor Bank; Tumor Immunity; Tumor-Derived; Tumor-infiltrating immune cells; Variant; Work; actionable mutation; cancer cell; cancer therapy; comparative; genetic variant; immunotherapy clinical trials; improved; in vivo; innovation; neoantigens; novel; precision medicine; prospective; recruit; response; targeted treatment; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY Inter-tumoral heterogeneity – the fact that every tumor has distinct genetic, epigenetic, and stromal features – poses a challenge for precision cancer therapy. While genetic variants that influence a tumor’s response to targeted therapy (i.e. “actionable mutations”) have received great attention, comparatively less is known about the causes of variation in the tumor microenvironment (TME). Nevertheless, such variation in the TME is likely to be of critical importance, as prior work has shown that the response to immunotherapy correlates with the abundance of T cells and other immune populations within a tumor [1,2]. We and others have shown, in the context of pancreatic ductal adenocarcinoma (PDA), that tumor-derived factors shape the microenvironment in vivo, dictating the relative abundance of different stromal populations. For example, tumor-derived GM-CSF recruits myeloid cells to the tumor, fostering an immunosuppressive environment [3,4], while tumor-derived Sonic Hedgehog causes an accumulation of myofibroblasts and other changes in the TME [5,6]. However, additional cancer cell-derived factors that act in similar fashion remain to be identified, representing an unexploited source of novel targets. In our preliminary work, we found that human PDA exhibits a wide spectrum of immune activity. Surprisingly, and in contrast to other tumor types, the presence or absence of an active immune signature was unrelated to the neo-antigen burden of a given tumor. We therefore hypothesize that cancer cell-intrinsic factors critically shape the immune microenvironment and drive immune heterogeneity. We further hypothesize that (i) a tumor’s immune makeup determines its response to immunotherapy and (ii) anti-tumor responses can be improved by modulating the immune infiltrate. Here, we propose an innovative approach to delineate the biology of immune heterogeneity in PDA, including novel implantable and genetically engineered mouse models studied in parallel with samples from an extensive tumor bank and prospectively collected from two clinical immunotherapy trials. Cellular, molecular, and clinical consequences of inter-tumoral heterogeneity will be assessed in the context of response to immunotherapy. Our ultimate goal is to understand and manipulate the immune microenvironment in PDA for therapeutic benefit, and we will approach this goal through the following three interrelated Specific Aims: Aim 1. Identify the molecular mechanism(s) underlying heterogeneity of immune infiltration Aim 2. Assess the impact of immune heterogeneity on the response to immunotherapy Aim 3. Elucidate the causes and consequences of immune heterogeneity in human PDA

项目总结 肿瘤间的异质性--每个肿瘤都有不同的遗传、表观遗传和间质 特征-对精确的癌症治疗提出了挑战。而影响肿瘤的基因变异 对靶向治疗的反应(即“可操作的突变”)受到了极大的关注，相对较少。 了解肿瘤微环境(TME)变化的原因。然而，这种变化在 TME可能是至关重要的，因为先前的研究表明，对免疫治疗的反应 与肿瘤内T细胞和其他免疫群体的丰度相关[1，2]。我们和其他人 已经表明，在胰腺导管腺癌(PDA)的背景下，肿瘤衍生因素塑造了 体内的微环境，决定了不同基质种群的相对丰度。例如, 肿瘤来源的GM-CSF向肿瘤招募髓系细胞，培养免疫抑制环境[3，4]， 而肿瘤来源的Sonic Hedgehog导致TME中肌成纤维细胞的积聚和其他变化 [5，6]。然而，其他以类似方式发挥作用的癌细胞衍生因子仍有待确定， 代表了一个未被开发的新目标来源。在我们的初步工作中，我们发现人类掌上电脑 表现出广泛的免疫活性。令人惊讶的是，与其他类型的肿瘤相比， 缺乏主动免疫信号与特定肿瘤的新抗原负荷无关。 因此，我们假设癌细胞的内在因素对免疫系统的形成起关键作用。 微环境和驱动免疫异质性。我们进一步假设：(I)肿瘤的免疫 化妆品决定其对免疫疗法的反应和(Ii)抗肿瘤反应可以通过以下方法改善 调节免疫渗透。在这里，我们提出了一种创新的方法来描绘生物 PDA中的免疫异质性，包括研究的新型可植入和基因工程小鼠模型 与来自一个广泛的肿瘤库的样本平行，并预期从两个临床 免疫疗法试验。肿瘤间异质性的细胞、分子和临床后果将是 在免疫治疗反应的背景下进行评估。我们的最终目标是理解和操纵 PDA中的免疫微环境对治疗有益，我们将通过以下方式实现这一目标 三个相互关联的具体目标： 目的1.确定免疫渗透异质性的分子机制(S) 目的2.评估免疫异质性对免疫治疗反应的影响 目的3.阐明人PDA免疫异质性的原因和后果