Targeting Dectin-2 on Tumor-associated Macrophages for the Treatment of Cancer

项目摘要/摘要 背景：免疫疗法已成为最有前景的治疗方法之一。 癌症。不幸的是，大量的患者和常见的肿瘤类型对现有的 免疫疗法。肿瘤相关巨噬细胞(TAMs)，它在许多癌症中聚集并抑制 抗肿瘤免疫，很可能是造成这个问题的原因。 假设和目标：基于令人鼓舞的初步数据，我们假设 Dectin-2是一种模式识别受体，在某些肿瘤中由TAMs高度表达，可以重新编程 TAMs转化为强大的抗原提呈细胞，能够诱导对多种癌症的免疫力。我们的 目的是通过分析天然和抗肿瘤的免疫和抗肿瘤作用来验证这一假说。 在小鼠癌症模型中合成Dectin-2激动剂。 具体目标：目标1：分析调节Dectin-2表达的因素及其机制 Dectin-2激动剂重新编程TAMs并诱导抗肿瘤免疫。目的2：评价黄曲霉毒素的抗肿瘤作用 天然Dectin-2激动剂，单独或与其他药物联合使用，治疗一系列侵袭性癌症。目标 3：合成Dectin-2糖肽激动剂并评价其单独和联合抗肿瘤活性 和其他特工在一起。目的4：构建肿瘤靶向抗体-糖肽偶联物并对其进行评价 功能和治疗效果。 研究设计与方法：由于TAMs在某些肿瘤中很少表达Dectin-2或不表达Dectin-2，我们将分析 天然Dectin-2激动剂对GM-CSF诱导的TAMs中Dectin-2表达的影响 这些激动剂的抗肿瘤作用将在小鼠的胰腺、乳房、结肠、肺和 Dectin-2表达谱的皮肤癌，作为单一疗法或联合GM-CSF 以及其他被证明可以增强Dectin-2激动剂在我们的小鼠模型中的疗效的药物。质量细胞术 而最近发展起来的信息学工具将被用来分析Dectin-2配体对抗病毒作用的影响 多种组织中的肿瘤免疫反应。为了产生更有效和更适用于临床的治疗方法， 将使用新的合成方法来生产成分定义的Dectin-2配体，并对其进行优化 对于的激活。这些合成的Dectin-2配体中最有效的将与肿瘤偶联- 增强肿瘤递送和介导的肿瘤细胞杀伤的靶向抗体及其 安全性和有效性评估。 预期结果和影响：我们预计这些实验将证明，在 TAMS可诱导对多种肿瘤的免疫，包括对检查点封锁具有抵抗力的肿瘤， Dectin-2激动剂单独使用或与其他抗肿瘤药物联合使用可以诱导持久的肿瘤 回归。这些激动剂中最有希望的将是临床开发的候选药物。

PROJECT SUMMARY/ABSTRACT Background: Immunotherapy has emerged as one of the most promising approaches for the treatment of cancer. Unfortunately, a large number of patients and common tumor types do not respond to existing immunotherapies. Tumor-associated macrophages (TAMs), which accumulate in many cancers and suppress anti-tumor immunity, likely contribute to this problem. Hypothesis and Objective: Based on encouraging preliminary data, we hypothesize that engagement of Dectin-2, a pattern recognition receptor that is highly expressed by TAMs in certain tumors, can reprogram TAMs into potent antigen-presenting cells capable of inducing immunity against a wide range of cancers. Our objective is to validate this hypothesis by analyzing the immunological and anti-tumor effects of natural and synthetic Dectin-2 agonists in mouse models of cancer. Specific Aims: Aim 1: Analyze the factors that regulate Dectin-2 expression and the mechanisms by which Dectin-2 agonists reprogram TAMs and induce anti-tumor immunity. Aim 2: Assess the anti-tumor effects of natural Dectin-2 agonists, alone and in combination with other agents, on a range of aggressive cancers. Aim 3: Synthesize glycopeptide agonists of Dectin-2 and assess their anti-tumor activity alone and in combination with other agents. Aim 4: Construct tumor-targeted antibody-glycopeptide conjugates and evaluate their functional and therapeutic effects. Study Design and Methods: Since TAMs in some tumors express little or no Dectin-2, we will analyze the effects of natural Dectin-2 agonists on TAMs in the presence of GM-CSF, which induces Dectin-2 expression. The anti-tumor effects of the agonists will be studied in mouse models of pancreas, breast, colon, lung, and skin cancer with a spectrum of Dectin-2 expression, both as monotherapies and in combination with GM-CSF and other agents shown to enhance the efficacy of Dectin-2 agonists in our mouse models. Mass cytometry and recently developed informatics tools will be utilized to analyze the effects of Dectin-2 ligands on the anti- tumor immune response in multiple tissues. To generate more effective and clinically applicable therapies, a novel synthetic approach will be used to produce compositionally defined Dectin-2 ligands that are optimized for TAM activation. The most efficacious of these synthetic Dectin-2 ligands will be conjugated to tumor- targeted antibodies for purposes of enhanced tumor delivery and TAM-mediated tumor cell killing, and their safety and efficacy assessed. Expected Results and Impact: We expect these experiments to demonstrate that engaging Dectin-2 on TAMs induces immunity against a wide range of tumors, including tumors resistant to checkpoint blockade, and that Dectin-2 agonists used alone or in combination with other anti-tumor agents can induce durable tumor regression. The most promising of these agonists will be candidates for clinical development.