Natural Killer Cell Regulation by PRDM1 and IRF4/8

PRDM1 和 IRF4/8 的自然杀伤细胞调节

• 批准号: 8505619
• 负责人: KENNETH Lynn WRIGHT
• 金额: $ 31.47万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-18 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8505619
• 关键词: Address; Affect; Antigens; Binding; Biological; Cancerous; Cell Cycle Inhibition; Cell Death; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chronic; Combined Modality Therapy; Cytolysis; DNA Binding; Data; Disease; Equilibrium; Family member; Gene Expression; Gene Targeting; HDAC1 gene; HDAC4 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; IRF4 gene; Immune; Immune response; Inflammatory; Inhibition of Apoptosis; Knowledge; Light; Link; Lymphoma; MAPK1 gene; MS4A1 gene; Mantle Cell Lymphoma; Mediating; Mediator of activation protein; Molecular; NK Cell Activation; Natural Killer Cells; Neoplasms; Non-Hodgkin' s Lymphoma; PCNA gene; PRDM1 gene; Pathway interactions; Patients; Phenotype; Receptor Signaling; Regulation; Regulator Genes; Reporting; Repression; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Testing; Therapeutic; Therapeutic Uses; Transcription Elongation; Tumor Necrosis Factor Ligand Superfamily Member 6; Tumor Suppressor Proteins; Tumor-Derived; Up-Regulation; antibody-dependent cell cytotoxicity; base; cytokine; cytotoxicity; insight; killings; leukemia/lymphoma; neoplastic cell; novel strategies; pathogen; public health relevance; response; therapeutic target; tumor

DESCRIPTION (provided by applicant): Natural Killer (NK) cells are central mediators of the innate immune response and serve as a first line defense against pathogens and tumors. NK cells have an intrinsic ability to lyse targeted cells which is controlled by the balance of activating and inhibitory receptor signals. NK cells also kill through antibody- dependent cell-mediated cytotoxicity (ADCC). Rutuximab (anti-CD20) therapy induces NK cell mediated ADCC against some lymphomas including Mantle Cell Lymphoma (MCL). However, in MCL current therapies are not successful and the disease remains incurable. Histone deacetylase inhibitors (HDACi) also show therapeutic promise and can induce cell cycle inhibition and apoptosis in leukemia and non-Hodgkin's lymphoma. Combination of approaches to induce tumor death and an immune response against the tumor may prove more successful. However, HDACi treatment of patients exposes the patients NK cells to the compound. HDACi have been reported to inhibit NK cells although the mechanisms are unknown. Thus understanding NK cell regulation and response to HDACi in lymphoma will be important in developing targeted and effective combination therapies. NK activation is accompanied by multiple gene expression changes however the underlying regulatory mechanisms are only now being addressed. We discovered that PRDM1 (Blimp-1) is up-regulated upon activation of normal NK cells and evidence indicates that it regulates both cytokine secretion and proliferative capacity. PRDM1 is deleted or inactivated in NK neoplasms suggesting a tumor suppressor role. In addition our studies have revealed selective enhancement and repression of HDAC family member expression during NK cell activation. However, the mechanisms and direct targets of PRDM1 in NK cells and the impact of HDACs and HDACi on these activities remain unknown. We have also observed that IRF4 and IRF8 are both up-regulated in parallel with PRDM1. IRFs and PRDM1 share similar DNA binding specificity and can compete for binding at specific target genes. How PRDM1 HDACs and IRF combine to regulate NK cell function and proliferation is unknown. The hypothesis to be tested is that PRDM1 in balance with specific HDACs is crucial to regulating NK cell proliferation and activity against tumor cells, specifically MCL. Furthermore HDACi exposure may significantly affect NK cell activity and alter PRDM1 function. This hypothesis will be tested in Aim 1 by identifying the impact on NK function of PRDM1-mediated suppression of key regulatory genes; PCNA, MAPK1 and ELL3. In Aim 2 the role of specific HDAC family members in regulating NK function will be characterized. Lastly in Aim 3 the activity of NK cells from MCL patients and the impact of HDAC modulation in these cells will be assessed. Deciphering the role of PRDM1 in NK cells and the impact of histone deacetylase inhibition will shed new light on the regulation of NK function and reveal new potential therapeutic targets and therapeutic combinations to enhance NK activity in MCL.

描述（由申请人提供）：天然杀手（NK）细胞是先天免疫反应的中心介体，并作为针对病原体和肿瘤的第一线防御。 NK细胞具有固定靶向细胞的固有能力，该能力由激活和抑制受体信号平衡控制。 NK细胞还通过抗体依赖性细胞介导的细胞毒性（ADCC）杀死。 rutuximab（抗CD20）疗法可诱导NK细胞介导的ADCC，以针对包括地幔细胞淋巴瘤（MCL）在内的某些淋巴瘤。但是，在MCL中，当前疗法并不成功，并且该疾病仍然无法治愈。组蛋白脱乙酰基酶抑制剂（HDACI）也表现出治疗的前景，可以诱导白血病和非霍奇金淋巴瘤中的细胞周期抑制和凋亡。诱导肿瘤死亡的方法和针对肿瘤的免疫反应的结合可能会更成功。但是，HDACI治疗患者将患者NK细胞暴露于该化合物。据报道，HDACI抑制NK细胞，尽管该机制尚不清楚。因此，了解NK细胞调节和对HDACI淋巴瘤中HDACI的反应将在开发有效和有效的联合疗法中很重要。 NK激活伴随着多种基因表达变化，但是潜在的调节机制直到现在才被解决。我们发现PRDM1（Blimp-1）在正常NK细胞激活后被上调，证据表明它调节了细胞因子的分泌和增殖能力。在NK肿瘤中删除或灭活PRDM1，表明抑制肿瘤的作用。此外，我们的研究表明，在NK细胞激活期间，HDAC家族成员表达的选择性增强和抑制。但是，NK细胞中PRDM1的机制和直接靶标以及HDAC和HDACI对这些活动的影响尚不清楚。我们还观察到IRF4和IRF8都与PRDM1并行上调。 IRF和PRDM1具有相似的DNA结合特异性，并且可以在特定靶基因上竞争结合。 PRDM1 HDAC和IRF如何组合以调节NK细胞功能和增殖尚不清楚。要检验的假设是，与特定HDAC平衡的PRDM1对于调节NK细胞增殖和针对肿瘤细胞的活性至关重要。此外，HDACI暴露可能会显着影响NK细胞活性并改变PRDM1功能。该假设将通过确定对PRDM1介导的关键调节基因抑制的NK功能的影响来检验。 PCNA，MAPK1和ELL3。在AIM 2中，将表征特定的HDAC家族成员在调节NK功能中的作用。最后，将评估来自MCL患者的NK细胞的活性以及HDAC调节对这些细胞的影响。解解PRDM1在NK细胞中的作用以及组蛋白脱乙酰基酶抑制的影响将为NK功能的调节提供新的启示，并揭示了新的潜在治疗靶标和治疗组合，以增强MCL的NK活性。