Title page for ETD etd-04132010-110934


Type of Document Dissertation
Author Dibra, Denada
URN etd-04132010-110934
Title Revealing the Role of Receptor WSX1: a Double-edged Sword in Tumor Progression
Degree Doctor of Philosophy (Ph.D.)
Department Comparative Biomedical Sciences (Veterinary Medical Sciences)
Advisory Committee
Advisor Name Title
Li, Shulin Committee Chair
Barker, Steven A. Committee Member
Li, Shisheng Committee Member
Sehgal, Inder Committee Member
Jeyaseelan, Samithamby Dean's Representative
Keywords
  • WSX1
  • tumor
  • NKG2D
  • tolerance
  • T cell
  • IL27
Date of Defense 2010-04-01
Availability unrestricted
Abstract
Tumor initiation and progression are dependent on both aberrant gene expression in tumor cells and the communication between tumor cells and its micro- and systemic microenvironment. Many tumor suppressor genes and oncogenes have been characterized to suppress or promote tumor growth, but fewer genes in tumors are well-characterized as interacting with immune cells in the host to promote or inhibit tumor growth. The interleukin (IL) 27 receptor WSX1 is expressed in immune cells and induces an IL27-dependent immune response. Opposing this conventional dogma, our initial results reveal a much higher level of WSX1 expression in multiple types of epithelial tumor cells when compared to normal epithelial cells. These revelations suggest a role for WSX1 in tumor development, and thus a possible target in cancer immune-therapy. Using genetically modified tumor cells, our studies show that the expression of WSX1 in tumor cells regulates the communication between tumor and host cells resulting in two different consequences. In both the cervical cell line TC1 and the squamous carcinoma cell line AT84, overexpression of WSX1inhibited tumorigenicity both in vivo and in vitro. Sensitizing NK cell-mediated surveillance through upregulation of NKG2D ligands in tumor cells is the underlying mechanism by which WSX1 inhibits tumor growth. Further investigations into other cell lines, such as colon cancer (CT26) and Lewis Lungs Carcinoma (LLC), confirmed the role of WSX1 as a tumor suppressor in vitro. In contrast to the role that WSX1 plays in the aforementioned cells, aggressive LLC and melanoma AGS tumor cells expressing WSX1 grow faster than the control cohorts. These studies reveal that the principal mechanism by which WSX1 promotes tumor growth is the inhibition of T cell proliferation and production of the effector cytokine IFNγ both in the tumor microenvironment and distal lymphatic tissues. Our evidence reveals that this effect is initiated via direct tumor cell and immune cell contact. This important observation reveals a new pathway of tumor-host interaction, which will ultimately lead to better strategies in immune therapy to reverse tumor tolerance.
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