Natural Killer Cell Regulation by PRDM1 and IRF4/8

描述(申请人提供)：自然杀伤(NK)细胞是先天免疫反应的中心媒介，是抵御病原体和肿瘤的第一道防线。NK细胞有一种固有的杀伤靶细胞的能力，这种能力受激活和抑制受体信号的平衡控制。NK细胞也通过抗体依赖的细胞介导的细胞毒作用(ADCC)进行杀伤。Rutuximab(抗CD20)治疗诱导NK细胞介导的ADCC抗包括套细胞淋巴瘤(MCL)在内的一些淋巴瘤。然而，在MCL中，目前的治疗方法并不成功，这种疾病仍然无法治愈。组蛋白去乙酰酶抑制剂(HDACi)也显示出治疗的前景，可以诱导白血病和非霍奇金淋巴瘤的细胞周期抑制和细胞凋亡。将诱导肿瘤死亡的方法与针对肿瘤的免疫反应相结合，可能会被证明更成功。然而，HDACi治疗患者会使患者的NK细胞暴露在这种化合物中。HDACi对NK细胞有抑制作用，但其作用机制尚不清楚。因此，了解淋巴瘤中NK细胞的调节和对HDACi的反应对于开发有针对性的有效的联合治疗将是重要的。NK的激活伴随着多种基因表达的变化，然而其潜在的调控机制直到现在才被解决。我们发现PRDM1(Blimp-1)在正常NK细胞激活时上调，并且有证据表明它同时调节细胞因子的分泌和增殖能力。在NK肿瘤中，PRDM1被缺失或失活，提示其具有肿瘤抑制作用。此外，我们的研究还发现，在NK细胞激活过程中，HDAC家族成员的表达有选择性地增强和抑制。然而，PRDM1在NK细胞中的作用机制和直接靶点以及HDACs和HDACi对这些活性的影响尚不清楚。我们还观察到IRF4和IRF8都与PRDM1平行上调。IRFS和PRDM1具有相似的DNA结合特异性，可以竞争结合特定的靶基因。PRDM1、HDACs和IRF如何结合来调节NK细胞的功能和增殖尚不清楚。需要检验的假设是，PRDM1与特定的HDACs的平衡对于调节NK细胞的增殖和抗肿瘤细胞的活性至关重要，尤其是MCL。此外，HDACi暴露可能会显着影响NK细胞活性和改变PRDM1功能。这一假说将在目标1中通过确定PRDM1介导的关键调控基因--增殖细胞核抗原、MAPK1和ELL3的抑制对NK功能的影响来检验。在目标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，在目标3中，将评估来自MCL患者的NK细胞的活性以及HDAC对这些细胞的影响。阐明PRDM1在NK细胞中的作用以及组蛋白脱乙酰酶抑制对其的影响，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.