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

项目总结/摘要 背景：免疫疗法已成为治疗肿瘤的最有前途的方法之一。 癌不幸的是，大量的患者和常见的肿瘤类型对现有的化疗没有反应。 免疫疗法肿瘤相关巨噬细胞（TAM），在许多癌症中积累并抑制 抗肿瘤免疫可能是导致这个问题的原因。 假设和目的：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TAM高度表达， TAM转化为能够诱导针对多种癌症的免疫力的有效抗原呈递细胞。我们 目的是通过分析天然和天然抗肿瘤药物的免疫和抗肿瘤作用来验证这一假说。 在小鼠癌症模型中的合成Dectin-2激动剂。 具体目的：目的1：分析调节Dectin-2表达的因素及其机制， Dectin-2激动剂重编程TAM并诱导抗肿瘤免疫。目的2：评估抗肿瘤作用 天然Dectin-2激动剂单独或与其它药剂组合用于一系列侵袭性癌症。目的 3：合成Dectin-2的糖肽激动剂并评估其单独和组合的抗肿瘤活性 和其他探员目的4：构建肿瘤靶向抗体-糖肽偶联物，并评价其生物学活性 功能和治疗效果。 研究设计和方法：由于一些肿瘤中的TAM很少表达或不表达Dectin-2，我们将分析这些肿瘤中的TAM。 在诱导Dectin-2表达的GM-CSF存在下，天然Dectin-2激动剂对TAM的作用。 激动剂的抗肿瘤作用将在胰腺、乳腺、结肠、肺和胰腺癌的小鼠模型中进行研究。 具有Dectin-2表达谱的皮肤癌，作为单一疗法和与GM-CSF组合 以及显示在我们的小鼠模型中增强Dectin-2激动剂的功效的其它药剂。质谱细胞术 最近开发的信息学工具将用于分析Dectin-2配体对抗- 多种组织中的肿瘤免疫应答。为了产生更有效和临床适用的疗法， 一种新的合成方法将用于生产优化的组成确定的Dectin-2配体 用于TAM激活。这些合成的Dectin-2配体中最有效的将与肿瘤细胞缀合。 用于增强肿瘤递送和TAM介导的肿瘤细胞杀伤目的的靶向抗体， 评估安全性和有效性。 预期的结果和影响：我们希望这些实验能够证明， TAM诱导针对多种肿瘤的免疫，包括对检查点阻断具有抗性的肿瘤， 并且单独使用或与其它抗肿瘤剂组合使用的Dectin-2激动剂可以诱导持久的肿瘤 回归分析这些激动剂中最有前途的将是临床开发的候选者。

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.