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癌症的主要障碍 免疫疗法。这一探索性项目的目标是开发一种新的mrna？lide。 基于纳米粒(mRNA-LNP)的免疫治疗在胰腺中克服这一挑战 癌症，最致命的恶性肿瘤之一。目前，几乎没有有效的治疗方法。 胰腺癌。大多数胰腺癌对免疫检查点也有抵抗力 封锁。因此，需要新的治疗策略来靶向这种致命的癌症。多数 胰腺癌表现为高度免疫抑制的肿瘤微环境。 肿瘤浸润性效应细胞CD8+T细胞对提高患者存活率至关重要，但它们确实是 在大多数胰腺癌中不存在或稀疏，表明一种内在机制 这阻碍了T细胞的渗透和激活。我们最近发现，刺激器 干扰素基因(STING)在胰腺癌和其他癌症中是沉默的。因为STING函数 是刺激抗肿瘤T细胞反应的关键，我们的发现表明，刺痛沉默 导致免疫学上的“冷”TME。我们发现，重新激活刺痛会上调 细胞因子/趋化因子对促进T细胞在肿瘤内的渗透起关键作用。更多 重要的是，STING的重新激活可以特异性地杀死被STING沉默的癌细胞。因为肿瘤 死亡的癌细胞在体内释放的抗原可以被抗原提呈细胞吞噬，从而 产生全身抗肿瘤反应并放大杀瘤作用，我们假设 胰腺癌中SING的靶向重新激活可使免疫受抑的人恢复活力 TME，提高肿瘤免疫原性。在这个项目中，我们将开发mRNA-LNP来 特异性地将永久活性的刺痛突变体导入胰腺癌以支持T细胞 抗肿瘤细胞毒性。这种方法旨在克服传统诱骗的局限性。 激动剂，缺乏肿瘤特异性，对刺痛沉默的癌症无效。要定义 它们在激发抗肿瘤免疫方面的有效性，刺痛mRNA-LNP将在体外和 在一种原位同基因小鼠胰腺癌模型中，它忠实地概括了 胰腺癌的免疫生物学“冷”TME。我们还将结合STING mRNA-LNP 用PD-1阻断规避胰腺癌对免疫检查点的抵抗 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来克服免疫耐药并改进治疗方法 一系列不同的止痛癌症，对目前的治疗方法难以奏效。

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.