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.
Natural Killer cells have significant potential in multiple tumor types as active cellular agents in anti-tumor immune based therapies, including Rutuximab therapy in lymphoma. However the transcriptional mechanisms regulating Natural Killer cell function and response to histone deacetylase inhibitors are poorly understood. The results of this study will provide new insight on the regulation of NK function and reveal new potential therapeutic targets and therapeutic combinations to enhance NK activity against tumors.