A novel gene therapy approach targeting STING-silenced cold tumors

项目摘要 肿瘤免疫抑制是实现有效治疗癌症的主要障碍 免疫疗法这个探索性项目的目标是开发一种新的mRNA-脂质 纳米颗粒（mRNA-LNP）为基础的免疫疗法，以克服这一挑战，在胰腺癌 癌症，最致命的恶性肿瘤之一。目前，很少有有效的治疗方法可用于 胰腺癌大多数胰腺癌也对免疫检查点有抵抗力 封锁因此，需要新的治疗策略来靶向这种致命的癌症。最 胰腺癌显示出高度免疫抑制的肿瘤微环境（TME）。 肿瘤浸润效应CD 8 + T细胞对于改善患者存活率至关重要，但它们 在大多数胰腺癌中不存在或稀疏，表明内在机制 阻止T细胞浸润和激活我们最近发现， 干扰素基因（STING）在胰腺癌和其他癌症中沉默。因为STING函数 对于刺激抗肿瘤T细胞反应至关重要，我们的发现表明STING沉默 有助于免疫学上的“冷”TME。我们发现重新激活STING可以上调 细胞因子/趋化因子是促进肿瘤内T细胞浸润的关键。更 重要的是，STING的重新激活特异性地杀死STING沉默的癌细胞。因为肿瘤 体内垂死癌细胞释放的抗原可被抗原呈递细胞吞噬， 产生全身抗肿瘤反应并增强杀肿瘤作用，我们假设， 靶向重新激活胰腺癌中的STING可以激活免疫抑制的 TME和提高肿瘤免疫原性。在这个项目中，我们将开发mRNA-LNP， 特异性递送永久活性STING突变体到胰腺癌中以支持T细胞 抗肿瘤细胞毒性。这种方法旨在克服传统STING的局限性 激动剂，缺乏肿瘤特异性，在STING沉默的癌症中不起作用。以限定 它们在刺激抗肿瘤免疫中的功效，将在体外测试STING mRNA-LNP， 在原位同基因小鼠胰腺癌模型中，其忠实地概括了 胰腺癌的免疫生物学“冷”TME。我们还将结合联合收割机STING mRNA-LNP 用PD-1阻断来规避胰腺癌对免疫检查点的耐药性 治疗和刺激协同抗肿瘤活性。这些临床前研究有可能 开发一种新的免疫疗法，以克服免疫耐药性，并改善治疗 一系列STING沉默的癌症对目前的疗法是难治的。

Project Summary Tumor immune suppression represents a major obstacle in achieving effective cancer immunotherapy. The goal of this exploratory project is to develop a novel mRNA-lipid nanoparticle (mRNA-LNP)-based immunotherapy to overcome this challenge in pancreatic cancer, one of the deadliest malignancies. Currently, few effective treatments are available for pancreatic cancer. The majority of pancreatic cancers are also resistant to immune checkpoint blockade. Thus, novel therapeutic strategies are needed to target this lethal cancer. Most pancreatic cancers display a highly immunosuppressive tumor microenvironment (TME). Tumor-infiltrating effector CD8+ T cells are critical for improved patient survival, and yet they are either absent or sparse in the majority of pancreatic cancers, indicating an intrinsic mechanism that impedes T cell infiltration and activation. We recently discovered that Stimulator of Interferon Genes (STING) is silenced in pancreatic and other cancers. Because STING function is critical for stimulating antitumor T cell responses, our finding suggests that STING silencing contributes to the immunologically “cold” TME. We found that reactivating STING upregulates cytokines/chemokines that are crucial for promoting intratumoral T cell infiltration. More importantly, reactivation of STING specifically kills STING-silenced cancer cells. Because tumor antigens released by dying cancer cells in vivo could be engulfed by antigen-presenting cells to generate systemic antitumor response and amplify tumoricidal effect, we hypothesize that targeted reactivation of STING in pancreatic cancer could invigorate the immune-dampened TME and improve tumor immunogenicity. In this project, we will develop mRNA-LNP to specifically deliver permanently active STING mutants into pancreatic cancer to bolster T cell antitumor cytotoxicity. This approach aims to overcome the limitations of traditional STING agonists, which lack tumor specificity and do not work in STING-silenced cancers. To define their efficacy in stimulating antitumor immunity, the STING mRNA-LNP will be tested in vitro and in an orthotopic syngeneic murine pancreatic cancer model, which faithfully recapitulates the immunobiologically “cold” TME of pancreatic cancer. We will also combine STING mRNA-LNP with PD-1 blockade to circumvent pancreatic cancer resistance to the immune checkpoint therapy and spur synergistic antitumoral activity. These preclinical studies have the potential for developing a novel immunotherapy to overcome immune resistance and improve treatments for a diverse array of STING-silenced cancers that are refractory to current therapies.