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Combination Therapies with Interleukin-21 in Chronic Lymphocytic Leukemia

Browning, Rebekah L.
http://orcid.org/0000-0003-2818-7375
http://rave.ohiolink.edu/etdc/view?acc_num=osu1429719855

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, with over 15,000 new cases diagnosed in the United States each year. CLL is characterized by an accumulation of malignant B cells and is associated with severe immune compromise, making infection a leading cause of morbidity and mortality in this population. Unfortunately, most frontline therapies for CLL exacerbate immune compromise. It is of great interest to develop treatment options that target the malignancy while sparing or even enhancing immune function. Interleukin-21 (IL-21) has emerged as one such candidate. IL-21 is a pleiotropic immune-modulating cytokine that is produced primarily by Th17, T follicular helper, (Tfh) and natural killer T (NKT) cells. IL-21 is of particular interest for therapy of CLL because it is directly cytotoxic to a subset of CLL B cells. However, effective cytotoxicity correlates with level of expression of the IL-21 receptor (IL-21R) on the tumor cells, and this expression is highly heterogeneous between patients. Thus, combining IL-21 with other treatments that increase IL-21R expression could result in a more effective therapeutic profile. CpG oligodeoxynucleotides (ODNs) have been demonstrated to increase IL-21R expression and enhance IL-21-mediated cytotoxicity in CLL cells. However, the mechanism by which CpG ODNs upregulate IL-21R has not been elucidated. Sp1 may be involved in constitutive expression of IL-21R but is not responsible for CpG ODN-mediated upregulation of IL-21R. Treatment of CLL cells with NF-κB inhibitor Bay 11 abrogated CpG ODN-mediated upregulation of IL-21R, indicating that CpG ODN activation of NF-κB is responsible for the enhanced expression of IL-21R. Lenalidomide is an immunomodulatory drug that, although not directly cytotoxic to CLL cells, has demonstrated efficacy against CLL in clinical trials, most likely through enhanced immune function and alteration of microenvironment interactions. Lenalidomide induces IL-21R in CLL B cells. In addition, lenalidomide induces production of IL-21 in T cells, whether from healthy volunteers or CLL patients. Treatment of CLL cells with the combination of lenalidomide and IL-21 enhanced IL-21-mediated cytotoxicity. This combination is associated with induction of p21 and the pro-apoptotic protein Bid. In addition, combined lenalidomide and IL-21 leads to a decrease in Lck, which is involved in pro-survival B cell receptor (BCR) signaling in CLL cells. Lenalidomide combined with IL-21 leads to reduced phosphorylation of SYK and PLCγ2, indicating that the combination reduces BCR signaling. These findings demonstrate a new potential combination therapy for CLL. Together, these studies enhance our understanding of the regulation of IL-21R and can contribute to development of rational combination therapies with both direct anti-tumor effects and enhanced immune function.
John Byrd (Advisor)
Natarajan Muthusamy (Advisor)
William Carson, III (Committee Member)
Susheela Tridandapani (Committee Member)
149 p.
Biomedical Research; Immunology
CLL; IL-21; lenalidomide; CpG ODN

Recommended Citations

Citations

  • Browning, R. L. (2015). Combination Therapies with Interleukin-21 in Chronic Lymphocytic Leukemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429719855

    APA Style (7th edition)

  • Browning, Rebekah. Combination Therapies with Interleukin-21 in Chronic Lymphocytic Leukemia. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1429719855.

    MLA Style (8th edition)

  • Browning, Rebekah. "Combination Therapies with Interleukin-21 in Chronic Lymphocytic Leukemia." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429719855

    Chicago Manual of Style (17th edition)

osu1429719855
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This open access ETD is published by The Ohio State University and OhioLINK.