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

基本信息

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
项目类别：
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&apos 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

项目摘要

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屏障的新型药物改善胰腺导管腺癌（PDAC）患者临床结果的潜力。我们发现靶向调节 mRNA 翻译的 MNK 激酶，增加 CD8+ T 细胞浸润和表达 T 细胞化学引诱剂。然而，MNK 抑制剂会诱导肿瘤相关巨噬细胞 (TAM) 表达免疫抑制蛋白 Arginase-1，表明 MNK 抑制剂极化 TAM 从而导致 CD8+ T 细胞精疲力尽。本申请的主要目的是确定 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功能。中心假设是靶向 MNK 激酶通路可以克服 CD8+ T 细胞浸润的免疫屏障。一秒钟假设 MNK 抑制剂表现出与克服该问题的疗法具有协同抗肿瘤反应 CD8+ T 细胞耗竭。提出了两个具体目标：1) 确定 MNK 激酶的机制癌细胞中的通路限制了 PDAC 肿瘤中 CD8+ T 细胞的浸润。 2）确定MNK通路的作用 TAM 及其对 PDAC 肿瘤中浸润性 CD8+ T 细胞效应功能的调节。在第一个下目标是，针对 PDAC 细胞中的 MNK 通路增加 T 细胞化学引诱物的机制将进行评估，重点关注下游 MNK 靶标 hnRNPA1 的作用。靶向 hnRNPA1 的效果还将在同基因原位小鼠模型中评估癌细胞中 CD8+ T 细胞浸润的情况。在其他研究表明，MNK 抑制剂和抗 PD-1 抗体联合治疗对 CD8+ T 细胞浸润和激活将在 PDAC 的 KPC 转基因小鼠模型中进行评估。对于第二个目标是巨噬细胞中 MNK 激酶和 MNK 效应子 hnRNPA1 对它们的作用的贡献将评估 CD8+ T 细胞效应功能的极化和调节。联合MNK的效果还将评估人 PDAC 肿瘤离体切片培养物中的 Arginase-1 抑制剂。另外研究，MNK 抑制剂、抗 PD-1 抗体和精氨酸酶 1 抑制剂三联疗法的功效将在 KPC 转基因和同基因原位小鼠模型中进行评估。有几个该提案中的创新要素，包括关于 MNK 激酶途径在调节 CD8+ T 细胞浸润和效应功能、独特的实验方法和新颖的治疗方法增强 PDAC 患者免疫治疗反应的方法。这项拟议的研究意义重大因为它将具有重要的临床转化意义，并应导致开发针对 PDAC 患者的基于机制的新型联合疗法。