Role of MNK kinase pathway in regulating tumor immune microenvironment in pancreatic cancer

MNK激酶通路在胰腺癌肿瘤免疫微环境调节中的作用

• 批准号: 10357033
• 负责人: Hidayatullah G. Munshi
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357033
• 关键词: 3' Untranslated Regions; Antitumor Response; Binding; CD8-Positive T-Lymphocytes; CTLA4 gene; CXCL10 gene; CXCL9 gene; Cellular Immunity; Cellular immunotherapy; Characteristics; Chemotactic Factors; Clinical; Clinical Research; Combined Modality Therapy; Development; Elements; Enzymes; Eukaryotic Initiation Factors; Genes; Genetic Translation; Goals; Health; Human; Immune response; Immunologics; Immunosuppression; Immunotherapy; Infiltration; Lead; Malignant neoplasm of pancreas; Mediating; Mission; Outcome; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Proteins; Reaction; Regimen; Regulation; Reporting; Research; Role; Slice; Solid Neoplasm; T-Lymphocyte; Testing; Transgenic Mice; Transgenic Organisms; Tumor-associated macrophages; Tumor-infiltrating immune cells; United States Department of Veterans Affairs; Veterans; anti-PD1 antibodies; arginase; base; cancer cell; cell type; chemokine; cytokine; effector T cell; efficacy evaluation; exhaustion; expectation; improved; improved outcome; in vivo; inhibitor; innovation; insight; interest; macrophage; mouse model; novel; novel therapeutic intervention; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; programmed cell death ligand 1; programmed cell death protein 1; protein expression; response; targeted treatment; therapy resistant; trafficking; tumor; tumor growth; tumor-immune system interactions

Novel agents that can overcome the immunological barrier to CD8+ T cell infiltration and effector function have the potential to improve clinical outcomes for pancreatic ductal adenocarcinoma (PDAC) patients. We have found that targeting MNK kinases, which regulate mRNA translation, increases CD8+ T cell infiltration and expression of T cell chemo-attractants. However, MNK inhibitors induce tumor-associated macrophages (TAMs) to express the immunosuppressive protein Arginase-1, suggesting that MNK inhibitors polarize TAMs to cause CD8+ T cell exhaustion. The main objective in this application is to identify mechanisms by which the MNK kinase pathway regulates tumor infiltration by CD8+ T cells and modulates their effector function. The central hypothesis is that targeting the MNK kinase pathway can overcome the immunological barriers to CD8+ T cell infiltration. A second hypothesis is that MNK inhibitors demonstrate synergistic anti-tumor responses with therapies that overcome CD8+ T cell exhaustion. Two specific aims are proposed: 1) Determine the mechanism by which the MNK kinase pathway in cancer cells limits CD8+ T cell infiltration in PDAC tumors. 2) Determine the role of the MNK pathway in TAMs and its regulation of the effector function of infiltrating CD8+ T cells in PDAC tumors. Under the first aim, the mechanisms by which targeting the MNK pathway in PDAC cells increases T cell chemo-attractants will be evaluated, focusing on the role of the downstream MNK target hnRNPA1. The effects of targeting hnRNPA1 in cancer cells on CD8+ T cell infiltration will also be assessed in the syngeneic orthotopic mouse model. In additional studies, the effects of the combination therapy with a MNK inhibitor and an anti-PD-1 antibody on CD8+ T cell infiltration and activation will be evaluated in the KPC transgenic mouse model of PDAC. For the second aim, the contribution of MNK kinases and the MNK effector hnRNPA1 in macrophages to their polarization and modulation of the CD8+ T cell effector function will be evaluated. The effects of combining MNK and Arginase-1 inhibitors in ex vivo slice cultures of human PDAC tumors will also be assessed. In additional studies, the efficacy of the triple regimen of a MNK inhibitor, an anti-PD-1 antibody, and an Arginase-1 inhibitor will be evaluated in the KPC transgenic and the syngeneic orthotopic mouse models. There are several innovative elements in this proposal, including novel concepts on the role of the MNK kinase pathway in regulating CD8+ T cell infiltration and effector function, unique experimental approaches, and novel therapeutic approaches to enhance immunotherapy responses in PDAC patients. This proposed research is significant because it will have important clinical-translational implications and should result in the development of mechanism-based novel combination therapies for PDAC patients.

可以克服CD8+ T细胞浸润和效应功能的免疫障碍的新型药物具有 改善胰腺导管腺癌（PDAC）患者临床结局的潜力。我们找到了 调节mRNA翻译的靶向MNK激酶会增加CD8+ T细胞浸润和表达 T细胞化学吸引力。但是，MNK抑制剂诱导肿瘤相关巨噬细胞（TAM）表达 免疫抑制蛋白精氨酸酶-1，表明MNK抑制剂极化TAM引起CD8+ T细胞 精疲力尽。该应用程序的主要目的是确定MNK激酶途径的机制 调节CD8+ T细胞的肿瘤浸润并调节其效应子功能。中心假设是 靶向MNK激酶途径可以克服CD8+ T细胞浸润的免疫障碍。第二 假设MNK抑制剂证明了与克服的疗法的协同抗肿瘤反应 CD8+ T细胞耗尽。提出了两个具体目标：1）确定MNK激酶的机制 癌细胞中的途径限制了PDAC肿瘤中的CD8+ T细胞浸润。 2）确定MNK途径的作用 在TAM中，其调节PDAC肿瘤中浸润CD8+ T细胞的效应子功能。在第一个 目的，针对PDAC细胞中MNK途径的机制会增加T细胞化学吸引者 进行评估，重点是下游MNK靶标HNRNPA1的作用。靶向HNRNPA1的影响 在CD8+ T细胞浸润的癌细胞中，还将在同步原位小鼠模型中评估。在 其他研究，组合疗法与MNK抑制剂和抗PD-1抗体的影响对 CD8+ T细胞浸润和激活将在PDAC的KPC转基因小鼠模型中评估。为了 第二个目的是巨噬细胞中MNK激酶和MNK效应子HNRNPA1的贡献 将评估CD8+ T细胞效应函数的极化和调节。组合MNK的效果 还将评估人体PDAC肿瘤的离体切片培养物中的精氨酸酶-1抑制剂。附加 研究，MNK抑制剂三重方案的功效，抗PD-1抗体和精氨酸酶-1抑制剂的疗效 将在KPC转基因和合成原位小鼠模型中进行评估。有几个 该提案中的创新元素，包括有关MNK激酶途径在 调节CD8+ T细胞浸润和效应子功能，独特的实验方法和新型治疗 增强PDAC患者免疫疗法反应的方法。这项拟议的研究很重要 因为它将具有重要的临床翻译意义，并应导致发展 基于机理的PDAC患者的新型组合疗法。