Particulate Delivery of STING Agonist as Anti-cancer Immuotherapeutics and Cancer Microbiome

摘要 癌症是第二大死因，在美国，每4人中就有1人死于癌症。当前 肿瘤中PD-L1的表达在很大程度上影响肿瘤的免疫治疗，尤其是检查点阻断； PD-L1阳性表达有限的患者通常对免疫治疗反应较差。这些 研究结果表明，需要新的技术来治疗PD-L1耐药肿瘤。环状[G(3‘，5’)pA(3‘，5’)p](CGAMP) 最近出现了一种令人兴奋的新型疫苗佐剂，它可以顺序激活先天免疫。 响应和协调适应性免疫。肿瘤相关巨噬细胞(TAMs)，一种主要的免疫类型 肿瘤微环境中的细胞，是辅助治疗的有效靶点。微粒系统是理想的交通工具 针对肿瘤内的人群。此外，联合疗法对治疗肿瘤大有可为 预防和治疗。最重要的是，癌症微生物组的关键作用正受到越来越多的关注 用于癌症治疗。我们假设靶向TAMS的cGAMP颗粒佐剂可以增强抗肿瘤作用 PD-L1应答和耐药的免疫应答和逆转促肿瘤微环境 与关卡封锁和肿瘤切除相结合，提高抗肿瘤效率。 我们已经并将继续使用B16F10黑色素瘤(皮下和肺)测试这一假设 转移模型；PD-L1反应)和C3(1)TAG基底样癌(原位和自发性GEM 模型；PD-L1抗性)，并测试以下特定目的：目的1.刺激剂AS的颗粒递送 抗癌免疫治疗：(F99期)。我们优化了脂质体NP和Ace-DEX MP给药系统 CGAMP用于评估细胞摄取和M2-M1偏斜能力，并检测主要组织相容性 (MHC)基因和共刺激基因在体外的表达和细胞因子的产生。我们还对组织进行了调查 颗粒型cGAMPs在上述肿瘤模型中的分布及其抗肿瘤作用。目标2. STING激动剂颗粒递送作为抗癌免疫治疗药物的机制 联合治疗：(F99期)。我们将研究巨噬细胞、CD4和CD8T细胞以及NK细胞的作用 细胞在cGAMPs颗粒抗肿瘤反应中的作用我们还将监测长期存活率和肿瘤复发。 用颗粒状cGAMPs联合抗PD-L1抗体和肿瘤切除治疗上述肿瘤 提到了肿瘤模型。目的3.博士后研究方向(K00阶段)。我将继续追求我的兴趣 了解肠道微生物区系在宿主对癌症发生和发展的反应中的机制和功能作用 与此同时，治疗特别关注研究口腔微生物区系在头颈部反应中的作用 癌症治疗和修复。

Abstract Cancer ranks as the second leading cause of death, contributing to nearly 1 in every 4 death in the US. Current cancer immunotherapies, especially checkpoint blockade, is largely influenced by PD-L1 expression in tumors; and patients with limited PD-L1 positive expression are normally less responsive to the immunotherapy. These findings suggest new technologies are needed to for PD-L1 resistant tumors. Cyclic [G(3',5')pA(3',5')p] (cGAMP) has recently emerged as an exciting new class of vaccine adjuvants, which sequentially activate innate immune responses and orchestrate adaptive immunity. Tumor associated macrophages (TAMs), a major type of immune cells in tumor microenvironment, are a potent target for adjuvant therapy. Particulate systems are ideal vehicles for targeting TAM population within tumor. Additionally, combination therapy holds great promise for tumor prevention and treatment. Most important, the critical role of cancer microbiome is gaining increased interests for cancer therapy. We hypothesize that Particulate cGAMP adjuvants targeting TAMs can enhance anti-tumor immune response and reverse the pro-tumorigenic microenvironment in both PD-L1 responsive and resistant cancers, and improve the anti-tumor efficiency in combination with checkpoint blockade and tumor resection. We have tested and will continue to test the hypothesis using B16F10 melanoma (subcutaneous and lung metastasis models; PD-L1 responsive) and C3(1)Tag basal-like breast cancer (orthotopic and spontaneous GEM models; PD-L1 resistant), and test the following specific aims: Aim 1. Particulate delivery of STING agonist as anti-cancer immuotherapeutics: (F99 phase). We optimized liposomal NP and Ace-DEX MP delivery systems for cGAMP to evaluate the cellular uptake and M2->M1 skewing capacity, and detect major histocompatibility (MHC) gene and costimulatory gene expression and cytokine production in vitro. We also investigated the tissue distribution of particulate cGAMPs and their anti-tumor efficacy in above-mentioned tumor models. Aim 2. Mechanism by which particulate delivery of STING agonist acts an as anti-cancer immuotherapeutic and combination therapies: (F99 phase). We will study the role of macrophage, CD4+ and CD8+ T cells, and NK cells in anti-tumor response of particulate cGAMPs. We will also monitor long term survival and tumor recurrence by combination therapies of particulate cGAMPs with anti-PD-L1 antibodies and tumor resection in above- mentioned tumor models. Aim 3. The Postdoctoral Research Direction (K00 phase). I will pursue my interest in understanding the mechanism and functional role of gut microbiota in host response to cancer development and therapy, meanwhile, with a particular interest in studying the role of oral microbiota in response to head and neck cancer therapeutics and restoration.