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Thesis final Jingwei Lu.pdf (1.9 MB)

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Development of Effective Immunotherapy for Ovarian Cancer Using Adoptive gamma-delta T Cells and Small Targeting Molecules

Lu, Jingwei
http://rave.ohiolink.edu/etdc/view?acc_num=osu1366380793

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Ovarian cancer is the second leading cancer in women and the leading cause of death from gynecological cancer. Most ovarian cancer patients are diagnosed at advanced stages with no effective treatment. Human innate and adaptive immune system play a critical role in providing first line of defense against tumor development and regulating tumor progression. The gammadelta T cells, a sub-population in human lymphocytes, bears both the characteristics of innate and adaptive immunity, and was found to be infiltrated in tumor tissue in ovarian cancer patients. The infiltration of gammadelta T cells was found to be associated with a brief disease-free interval in advanced ovarian carcinomas. In my Ph.D. study, I mainly focus on illustrating the molecular mechanisms between the interaction of Vgamma2Vdelta2 T cells, a sub-population of gammadelta T cells, and ovarian tumor cells and explored its possible development of an efficient immunotherapy for ovarian cancer patients. In the first step of the study, we found that Vgamma2Vdelta2 T cells differentially reduced the proliferation and growth of several ovarian tumor cell lines. Upon co-culture with Vgamma2Vdelta2 T cells, A2780 cell line (resistant to Vgamma2Vdelta2 T cells-mediated lysis) showed reduced expression of cell-cycle related molecule and entered into equilibrium stage, which is characterized by reduced proliferation. The interaction between Vgamma2Vdelta2 T cells and A2780 was found to be partially mediated by NKG2D-MICA recognition. Up-regulation of pErk1/2 was found to be able to partially overcome the resistance of A2780 cells and made the A2780 cell line to move forward towards apoptosis when co-cultured with Vgamma2Vdelta2 T cells. In the second part of the study, we focused on illustrating the molecule mechanisms, which regulate the resistance characteristics of ovarian tumor cells towards Vgamma2Vdelta2 T cells, and, more specifically, the ATM/ATR signaling pathway, which lies on the upstream of pErk1/2. In this study, we found that down-regulation of ATM/ATR pathways induce down regulation of MICA in ovarian tumor cells resulting in resistance towards Vgamma2Vdelta2 T cells. Stimulating ATM/ATR pathway enhances the MICA expression and sensitizes resistance ovarian tumor cells towards Vgamma2Vdelta2 T cells mediated lysis. We further show that combining current approved chemotherapeutic drug Etoposide, which induces ATM phosphorylation along with Vgamma2Vdelta2 T cells promote the cytotoxicity of resistant ovarian tumor cells. These finding illustrate the detailed molecular signaling pathway that involved in regulating tumor cells to evade immune cells recognition and lysis. The study also indicated that drug promoting ATM signaling pathway might be sued as a combination therapy with Vgamma2Vdelta2 T cells for treating ovarian cancer.
Hiranmoy Das (Advisor)
Periannan Kuppusamy (Committee Member)
Sujit Basu (Committee Member)
Lai-Chu Wu (Committee Member)
Biology; Biomedical Research; Cellular Biology; Immunology; Medicine; Molecular Biology; Oncology

Recommended Citations

Citations

  • Lu, J. (2013). Development of Effective Immunotherapy for Ovarian Cancer Using Adoptive gamma-delta T Cells and Small Targeting Molecules [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1366380793

    APA Style (7th edition)

  • Lu, Jingwei. Development of Effective Immunotherapy for Ovarian Cancer Using Adoptive gamma-delta T Cells and Small Targeting Molecules. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1366380793.

    MLA Style (8th edition)

  • Lu, Jingwei. "Development of Effective Immunotherapy for Ovarian Cancer Using Adoptive gamma-delta T Cells and Small Targeting Molecules." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1366380793

    Chicago Manual of Style (17th edition)

osu1366380793
414
© 2013, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.