Molecular Determinants and Therapeutic Consequences of Immune Heterogeneity in Cancer

项目摘要 肿瘤间异质性-每个肿瘤具有不同的遗传、表观遗传和间质 功能-对精确的癌症治疗提出了挑战。虽然影响肿瘤生长的基因变异 对靶向治疗的反应（即"可操作的突变"）受到了极大的关注， 肿瘤微环境（TME）变异的原因。然而，这种变化在 TME可能至关重要，因为先前的工作表明，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，肿瘤衍生因子塑造了 在体内的微环境，决定了不同的基质群体的相对丰度。比如说， 肿瘤来源的GM-CSF将骨髓细胞募集到肿瘤中，培养免疫抑制环境[3，4]， 而肿瘤来源的Sonic Hedgehog引起TME中肌成纤维细胞的积累和其他变化， [5、6]。然而，以类似方式起作用的其他癌细胞衍生因子仍有待鉴定， 代表了新目标的未开发来源。在我们的初步工作中，我们发现人类的PDA 表现出广泛的免疫活性。令人惊讶的是，与其他肿瘤类型相比， 活性免疫标记的缺乏与给定肿瘤的新抗原负荷无关。 因此，我们假设癌细胞内在因素决定性地塑造了免疫系统。 微环境和驱动免疫异质性。我们进一步假设（i）肿瘤的免疫功能 组成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式改善： 调节免疫浸润。在这里，我们提出了一种创新的方法来描绘生物学的 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 与来自广泛肿瘤库的样品平行，并从两个临床试验中前瞻性收集 免疫治疗试验肿瘤间异质性的细胞、分子和临床后果将在 在对免疫疗法的反应的背景下评估。我们的最终目标是理解和操纵 免疫微环境在PDA的治疗效益，我们将通过以下途径达到这一目标 三个相互关联的具体目标： 目标1。确定免疫浸润异质性的分子机制 目标二。评估免疫异质性对免疫治疗应答的影响 目标3。阐明人类PDA免疫异质性的原因和后果

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