Open Access Thesis
Date of Award
Biochemistry and Molecular Biology
Cancer immunotherapy has had limited clinical efficacy partly because regulatory T cells (Treg) suppress the immune response to tumor-associated antigens. Inducible regulatory T cells (iTreg), which are converted from naÃ¯ve CD4 T cells by TGF-β, an abundant cytokine in the tumor microenvironment, may contribute to this immune suppression. Induction of Foxp3 by TGF-β is mediated by the transcription factor TIEG1 and abrogation of this protein prevents Foxp3 expression. We are testing the hypothesis that blockade of TIEG1 to prevent iTreg conversion will enhance immune response in DNA vaccination to the tumor associated antigen Her-2. Wild type and TIEG1 knockout mice in C57BL/6 background were immunized with three different antigens, then immune responses were compared. In TIEG1-/- mice, immunization with allogeneic spleen cells resulted in a stronger T cell response with comparable levels of antibody. Similarly, Her-2-expressing irradiated tumor cells induced a stronger anti-Her-2 T cell response in TIEG1-/- mice, without a significant difference in antibody levels. DNA vaccine encoding human Her-2 also induced a stronger T cell response but with reduced IgG antibody titers specifically in IgG1 and deficient switching to IgG2c. B cells in TIEG1-/- mice had adequate counts in vivo and they proliferated normally in vitro in response to PMA + Ionomycin stimulation. Foxp3+ cells had adequate numbers in TIEG1-/- mice whereas Myeloid Derived Suppressor Cells had stronger proliferation to PMA + Ionomycin stimulation. Initially tumors grew more slowly in TIEG1-/- mice but the difference disappeared later. A new sub strain of TIEG1-/- mice was derived that has similar T cell response but more severely impaired antibody response. Together, these data suggest an amplified T (but not B) cell response in TIEG1-/- mice, indicating pleiotropic immune modulating effects of TIEG1.
Cani, Andi, "Modulation Of Anti-Tumor Immune Response By Tgf-Β-Inducible Early Gene 1 (tieg1)" (2012). Wayne State University Theses. 202.