Natural Killer Cell Regulation by PRDM1 and IRF4/8

描述（由申请人提供）：自然杀伤（NK）细胞是先天免疫应答的中心介质，并作为对抗病原体和肿瘤的第一线防御。NK细胞具有裂解靶细胞的内在能力，其由活化和抑制受体信号的平衡控制。NK细胞还通过抗体依赖性细胞介导的细胞毒性（ADCC）杀伤。Rutuximab（抗CD 20）治疗诱导NK细胞介导的ADCC，以对抗某些淋巴瘤，包括套细胞淋巴瘤（MCL）。然而，在MCL中，目前的疗法并不成功，并且该疾病仍然无法治愈。组蛋白去乙酰化酶抑制剂（HDACi）也显示出治疗前景，并可诱导白血病和非霍奇金淋巴瘤的细胞周期抑制和凋亡。结合诱导肿瘤死亡和针对肿瘤的免疫反应的方法可能会更成功。然而，患者的HDACi治疗使患者的NK细胞暴露于化合物。HDACi已被报道抑制NK细胞，尽管机制尚不清楚。因此，了解淋巴瘤中NK细胞的调节和对HDACi的反应对于开发靶向和有效的联合疗法将是重要的。 NK细胞活化伴随着多个基因表达的变化，然而，潜在的调控机制现在才得到解决。我们发现PRDM 1（Blimp-1）在正常NK细胞活化后上调，并且有证据表明它调节细胞因子分泌和增殖能力。PRDM 1在NK肿瘤中缺失或失活，提示肿瘤抑制作用。此外，我们的研究揭示了在NK细胞活化过程中HDAC家族成员表达的选择性增强和抑制。然而，NK细胞中PRDM 1的机制和直接靶点以及HDAC和HDACi对这些活性的影响仍然未知。我们还观察到IRF 4和IRF 8都与PRDM 1平行上调。IRF和PRDM 1具有相似的DNA结合特异性，并且可以竞争结合特定的靶基因。PRDM 1 HDAC和IRF如何结合联合收割机来调节NK细胞功能和增殖尚不清楚。待检验的假设是PRDM 1与特异性HDAC平衡对于调节NK细胞增殖和针对肿瘤细胞（特别是MCL）的活性至关重要。此外，HDACi暴露可显著影响NK细胞活性并改变PRDM 1功能。将在目的1中通过鉴定PRDM 1介导的关键调控基因PCNA、MAPK 1和ELL 3的抑制对NK功能的影响来检验这一假设。在目的2中，将表征特定HDAC家族成员在调节NK功能中的作用。最后，在目标3中，将评估来自MCL患者的NK细胞的活性和HDAC调节对这些细胞的影响。解读PRDM 1在NK细胞中的作用和组蛋白脱乙酰酶抑制的影响将为NK功能的调节提供新的线索，并揭示新的潜在治疗靶点和治疗组合，以增强MCL中的NK活性。

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.