Engineered Nanoformulation for Immune-modulation in Cancer

免疫检查点（ICP）分子在肿瘤细胞上的表达与宿主免疫 细胞，特别是存在于肿瘤环境中的T细胞，对癌症治疗产生负面影响。 结果导致无效的肿瘤根除。数据显示化疗和放疗- 治疗在肿瘤细胞上诱导ICP蛋白，从而有助于肿瘤灭活 浸润性T细胞，导致不能宿主强大的抗肿瘤反应，并最终导致 治疗失败和疾病复发。因此，了解癌症药物如何影响 ICP将导致新的治疗策略的发展，可以绕过ICP介导的 治疗失败。其中一种方法是将免疫检查点抑制剂（ICPi） 其可以重新引发T细胞应答并增强抗癌药物的功效。 PI实验室和其他机构的研究表明， 抑制人抗原R（HuR），一种在人淋巴细胞中过表达的mRNA结合蛋白， 人癌细胞，导致生长抑制，转移减少， 动物生存。虽然这些发现支持推进HuR靶向治疗的临床应用， 翻译，PI的实验室最近偶然发现了siRNA- 使用基于脂质的纳米颗粒（HuR-NP）诱导的程序化HuR沉默 死亡配体（PD-L）1在肺癌细胞中的表达。PD-L1是几种ICP蛋白之一 当被肿瘤细胞表达时抑制T细胞功能。HuR-NP显著诱导PD-1表达。 人肺癌细胞株L1 mRNA和蛋白表达的研究分子研究表明 PD-L1启动子区的HuR结合位点。最后，HuR之间的负相关性 PD-L1在人肺癌组织中有表达。据我们所知，除了 从我们自己的观察报告中，没有先前的报告表明， HuR调节PD-L1和测试HuR纳米疗法与PD-L1免疫疗法治疗癌症。 在我们新发现的基础上，我们认为，将HuR纳米疗法与PD-L1结合， 免疫疗法将通过引发强免疫应答而显示出上级抗癌功效 缓解，减少疾病复发。我们将用三个目标来检验我们的假设：目标1。 确定靶向HuR的LNP联合抗PD-L1治疗的治疗获益 体外目标二。证明LNP靶向HuR治疗联合PD-L1 使用肺肿瘤模型的体内免疫治疗激发免疫应答并增强免疫应答。 抗肿瘤活性。目标3。研究LNP靶向HuR的分子机制 调节肺癌细胞中的PD-L1表达。

Expression of immune check point (ICP) molecules on tumor cells and the host immune cells, especially T-cells present in the tumor milieu, negatively impact the cancer treatment outcome resulting in inefficient tumor eradication. Data also exist showing chemo- and radio- therapy induce ICP proteins on tumor cells and thereby contributing to inactivation of tumor infiltrating T-cells, resulting in the inability to host a robust antitumor response and culminating in treatment failure, and disease recurrence. Hence, understanding how a cancer drug impacts ICP will lead to development of new therapeutic strategies that can circumvent ICP-mediated treatment failure. One such approach is to incorporate immune check point inhibitors (ICPi) which can rekindle T-cell response and enhance the efficacy of anticancer drugs. Studies from the PI's laboratory and others have demonstrated genetic and pharmacologic inhibition of the human antigen R (HuR), an mRNA-binding protein that is overexpressed in human cancer cells, results in growth inhibition, reduction in metastasis, and in increased animal survival. While these findings support advancing HuR-targeted therapy for clinical translation, the PI's lab has recently made a serendipitous discovery showing siRNA- mediated silencing of HuR using a lipid-based nanoparticle (HuR-NP) induced programmed death-ligand (PD-L)1 expression in lung cancer cells. PD-L1 is one among several ICP proteins which when expressed by tumor cells suppress T-cell function. HuR-NP markedly induced PD- L1 mRNA and protein expression in human lung cancer cell lines. Molecular studies showed HuR binding site in the promoter region of PD-L1. Finally, a negative correlation between HuR and PD-L1 expression was observed in human lung cancer tissues. To our knowledge, apart from our own observation reported herein, there are no prior reports demonstrating the ability of HuR to regulate PD-L1 and testing of HuR-nanotherapy with PD-L1 immunotherapy for cancer. On the basis of our novel findings, we posit that combining HuR-nanotherapy with PD-L1 immunotherapy will demonstrate superior anticancer efficacy by eliciting strong immune response, and reducing disease recurrence. We will test our hypothesis with three aims: Aim 1. Determine the therapeutic benefit of LNP targeting HuR in combination with anti-PD-L1 therapy in vitro. Aim 2. Demonstrate LNP targeted HuR treatment in combination with PD-L1 immunotherapy in in vivo using lung tumor models elicits immune response and enhanced antitumor activity. Aim 3. Investigate the molecular mechanism by which LNP targeting HuR modulates PD-L1 expression in lung cancer cells.