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Immune Attunement: Fortifying Anti-Tumor Immunity Via T Cell Co-Stimulation

Do, Priscilla
http://rave.ohiolink.edu/etdc/view?acc_num=osu1492568422442233

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Immune suppression is a hallmark of cancer that has gained recent unprecedented attention following dramatic responses with new immune based therapies. Many therapeutic strategies are employed to reverse suppression and utilize our natural biological defense against cancerous cells. The beauty of which, is demonstrated as a non-chemotherapeutic method for durable clinical benefit and potentially, a cure. Attunement of anti-tumor immunity rests largely on provocation of adaptive immunity and the ability of T cells to remember non-self and self-dangerous signals. The naive to effector T cell transition, accomplished through stimulation of the T cell receptor and co-stimulation through CD28, is critical for the development of this response. Presented here are two strategies in a B cell malignancy, Chronic Lymphocytic Leukemia (CLL), aimed at attunement of this T cell co-stimulatory node by influencing surrounding biological players. The first component of this dissertation identifies Cytotoxic T Lymphocyte Antigen 4 (CTLA-4), an antagonist of CD28, as a potential therapeutic target on tumor cells. Despite clinical utility in targeting CTLA-4 on T cells, its function on non-T cells remains unaddressed, especially in the context of therapy. We define an immunosuppressive role for tumor expressed CTLA-4 in CLL. A majority of primary CLL samples were intracellularly CTLA-4+. Co-culture with activated T cells induced surface expression of CTLA-4 on CLL B cells. CTLA-4 expression on CLL cell lines Mec1 and OSU-CLL decreased expression of the cognate ligand, CD80, on CD80+ cells with rescue upon CTLA-4 blockade. Co-culture of CTLA-4+ Mec1 and CTLA-4+ primary CLL cells with CD80-GFP+ cells revealed transfer of CD80-GFP into primary CLL and Mec1 cells, consistent with the ability of CTLA-4+ T cells to trans-endocytose CD80. Additionally, co-culture of T cells with Mec1 CTLA-4+ cells decreased IL2 production, signifying reduced co-stimulation. Finally, the role of CTLA-4 on disease progression and overall survival was tested in vivo using a newly generated mouse model. We present a novel paradigm that extends the immunosuppressive role for CTLA-4 beyond expression on T cells. The second component of this dissertation investigates a novel immunomodulatory drug, CC-122. Structurally, CC-122 is similar to Lenalidomide (Lena), a pleiotropic immune modulator approved for multiple myeloma, myelodysplastic syndrome, and mantle cell lymphoma that activates B, T, and NK cells. Unique to CLL therapy with Lena is a potentially fatal, dose-limiting toxicity known as tumor flare. Because Lena is hypothesized to work through restoration of T cell function, including promotion of co-stimulation, CC-122 and Lena were compared in this context. A key difference was discovered between CC-122 and Lena treated activated CLL T cells by gene expression analysis. CXCL13, a B cell chemoattractant, was > 3 fold increased with Lena v. CC-122. Overexpression of the CXCL13 receptor, CXCR5, in CLL but not MM may contribute to migration of CLL cells to the lymph nodes and tumor flare. Retaining the anti-tumor activity of Lena while mitigating toxicity is of clinical interest and critical to the development of CC-122. Overall, these studies reveal basic biological mechanisms in cancer immunology relevant to CLL and potentially other diverse malignancies.
Natarajan Muthusamy, PhD, DVM (Advisor)
John Byrd, MD (Advisor)
Virginia Sanders, PhD (Committee Member)
Gregory Lesinski, PhD (Committee Member)
212 p.
Biomedical Research; Immunology
CTLA-4; immune therapy; cancer; checkpoint blockade; CC-122

Recommended Citations

Citations

  • Do, P. (2017). Immune Attunement: Fortifying Anti-Tumor Immunity Via T Cell Co-Stimulation [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492568422442233

    APA Style (7th edition)

  • Do, Priscilla. Immune Attunement: Fortifying Anti-Tumor Immunity Via T Cell Co-Stimulation. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1492568422442233.

    MLA Style (8th edition)

  • Do, Priscilla. "Immune Attunement: Fortifying Anti-Tumor Immunity Via T Cell Co-Stimulation." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492568422442233

    Chicago Manual of Style (17th edition)

osu1492568422442233
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© 2017, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.