Epigenetic Modifiers to Augment the Immunogenicity of Chronic Lymphocytic Leukemia

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Dubovsky, Jason A.
Epigenetic; Histone; Leukemia; Lymphocyte; Methylation; T cell
thesis / dissertation description
Cancer cells employ a litany of immunosuppressive and immunevasive strategies to avoid detection and elimination by the various arms of the innate and adaptive immune system. Many hematologic and solid tumors progressively develop a specialized microenvironment which promotes tissue restructuring inflammation while masking the immune signature of the tumor cells themselves. Chronic lymphocytic leukemia, a malignancy of mature B lymphocytes must constantly balance on the precipice of immune recognition. A mature antigen presenting cell themselves, CLL clonal growth is dependent on the very interactions which, if effective, could potentially lead to their demise. To circumvent this, CLL clones set up unique signatures which promote immune recognition yet provide diversionary signals to the remaining immune armament resulting in profound immune dysfunction.While the aforementioned immune dysfunction is widespread, the B cell and T cell repertoire are severely impaired during leukemic progression. The lack of healthy B cells due to displacement by malignant B cells results in the obvious loss of an important antigen presenting cell as well as antibody-based immunity. Additionally, deficient interactions with T cells result in anergy and the preponderance of improperly polarized T lymphocytes which are impotent to eliminate both pathogens and leukemic cells. The result of such severe immune dysfunction is chronic infection and progressive disease which is the primary cause of death in CLL patients.Our research was focused on the premise that alleviating immune dysfunction and providing immunotherapeutic tools will significantly benefit CLL therapy. To this end we developed methods to improve the cellular interaction between CLL cells and T cells a critical step towards improving the antigen presentation capacity of the diseased B cell repertoire. We also identified a therapeutic strategy which can revert the anergic or improperly polarized state of T cells already in circulation allowing those cells to more effectively perform the effector functions necessary to fight pathogenic attack and malignant transformation. Finally, we identified a number of novel targets in CLL which could be used in a vaccinate-induce method to license the elimination of CLL cells by the patient's adaptive immune system. To achieve our goals we utilized a relatively new class of drugs called epigenetic modifiers which specifically alter the chromatin structure resulting in novel genetic signatures which are heritable over cellular generations. The unique properties of these drugs allow for the elicitation of suppressed genetic programs which, when properly controlled, have the potential to reassert healthy lymphocyte functions.Our studies provide a comprehensive therapeutic initiative which, by simultaneously alleviating the major causes of immune dysfunction in addition to facilitating the use of novel active immunotherapeutic strategies could potentially impact clinical therapy for CLL.