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

可以克服对CD 8 + T细胞浸润和效应子功能的免疫屏障的新型药物具有 改善胰腺导管腺癌（PDAC）患者临床结局的潜力。我们发现 靶向调节mRNA翻译的MNK激酶增加了CD 8 + T细胞的浸润和表达， T细胞化学引诱物。然而，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TAMs导致CD 8 + T细胞 疲惫不堪本申请的主要目的是鉴定MNK激酶途径的机制， 调节CD 8 + T细胞的肿瘤浸润并调节其效应子功能。核心假设是， 靶向MNK激酶途径可以克服对CD 8 + T细胞浸润的免疫屏障。第二 假设是MNK抑制剂与克服肿瘤的疗法表现出协同抗肿瘤反应 CD 8 + T细胞耗竭。提出了两个具体目标：1）确定MNK激酶 癌细胞中的CD 8 + T细胞通路限制了PDAC肿瘤中的CD 8 + T细胞浸润。2)确定MNK通路的作用 在TAMs中的作用及其对PDAC肿瘤中浸润性CD 8 + T细胞的效应子功能的调节。根据第一项 目的是，靶向PDAC细胞中的MNK途径增加T细胞化学引诱物的机制将 进行评估，重点是下游MNK靶点hnRNPA 1的作用。靶向hnRNPA 1的作用 还将在同基因原位小鼠模型中评估癌细胞中CD 8 + T细胞浸润。在 在其他研究中，使用MNK抑制剂和抗PD-1抗体的联合疗法对 将在PDAC的KPC转基因小鼠模型中评价CD 8 + T细胞浸润和活化。为 第二个目标是巨噬细胞中MNK激酶和MNK效应子hnRNPA 1对其功能的贡献。 将评价CD 8 + T细胞效应子功能的极化和调节。联合MNK的效果 和精氨酸酶-1抑制剂在人PDAC肿瘤的离体切片培养物中的作用。的额外 研究，MNK抑制剂、抗PD-1抗体和精氨酸酶-1抑制剂的三联方案的疗效 将在KPC转基因和同基因原位小鼠模型中进行评价。有几 本提案中的创新要素，包括关于MNK激酶途径在 调节CD 8 + T细胞浸润和效应子功能，独特的实验方法和新的治疗方法， 增强PDAC患者免疫治疗反应的方法。这项研究具有重要意义 因为它将具有重要的临床转化意义，并将导致 用于PDAC患者的基于机制的新型组合疗法。

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.