Agonist Anti-GITR Antibody Enhances Vaccine-Induced CD8+ T-Cell Responses and Tumor Immunity

Abstract

Immunization of mice with plasmids encoding xenogeneic orthologues of tumor differentiation antigens can break immune ignorance and tolerance to self and induce protective tumor immunity. We sought to improve on this strategy by combining xenogeneic DNA vaccination with an agonist antiglucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) monoclonal antibody (mAb), DTA-1, which has been shown previously both to costimulate activated effector CD4 + and CD8 + T cells and to inhibit the suppressive activity of CD4 + CD25 + regulatory T cells. We found that ligation of GITR with DTA-1 just before the second, but not the first, of 3 weekly DNA immunizations enhanced primary CD8 + T-cell responses against the melanoma differentiation antigens gp100 and tyrosinase-related protein 2/ dopachrome tautomerase and increased protection from a lethal challenge with B16 melanoma. This improved tumor immunity was associated with a modest increase in focal autoimmunity, manifested as autoimmune hypopigmentation. DTA-1 administration on this schedule also led to prolonged persistence of the antigen-specific CD8 + T cells as well as to an enhanced recall CD8 + T-cell response to a booster vaccination given 4 weeks after the primary immunization series. Giving the anti-GITR mAb both during primary immunization and at the time of booster vaccination increased the recall response even further. Finally, this effect on vaccine-induced CD8 + Tcell responses was partially independent of CD4 + T cells (both helper and regulatory), consistent with a direct costimulatory effect on the effector CD8 + cells themselves. (Cancer Res 2006; 66(9): 4904-12)

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

“…GITR) providing additional specificity to the CTLA-4/B7 interaction (Fig. 4) [48]. For example, the glucocorticoid-induced leucine zipper (GILZ) gene is an important, yet unstudied, IL-2-inhibiting transcriptional repressor showing high homology with ICER through its leucine-zipper region [15,49].…”

Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy

“…22 Interestingly, these mice also showed an increase in autoimmune hypopigmentation. 22 Together, these data indicate that treatment with agonistic anti-GITR, alone or as an adjunct to active immunization, increases the ability to break immune tolerance. Although there is some debate, recent studies indicate that this enhanced immune response is due to ligation of GITR on the effector cells, making them resistant to suppression, rather than on the Tregs themselves.…”

“…13,14,21 An antibody that has been extensively tested in mice targets the glucocorticoid-induced tumor necrosis factor receptor (GITR). [22][23][24][25][26][27][28] GITR, a member of the tumor necrosis factor receptor superfamily, is constitutively expressed on Tregs but it is also expressed at low levels on multiple immune cells, including T cells, natural killer cells and B cells in which it is upregulated on activation. 7,23,[29][30][31] Treatment of mice with an agonistic anti-GITR mAb (anti-GITR), clone DTA-1, alone has been shown to cause exacerbated autoimmune disease in susceptible mice and enhanced anti-viral and anti-tumor immune responses in disease-bearing animals.…”

“…7,23,[29][30][31] Treatment of mice with an agonistic anti-GITR mAb (anti-GITR), clone DTA-1, alone has been shown to cause exacerbated autoimmune disease in susceptible mice and enhanced anti-viral and anti-tumor immune responses in disease-bearing animals. 22,[24][25][26][27][28] When combined with DNA immunization against xenogeneic melanoma-related antigens, DTA-1-treated mice showed increased T-cell responses and protection from tumor challenge. 22 Interestingly, these mice also showed an increase in autoimmune hypopigmentation.…”

“…22,[24][25][26][27][28] When combined with DNA immunization against xenogeneic melanoma-related antigens, DTA-1-treated mice showed increased T-cell responses and protection from tumor challenge. 22 Interestingly, these mice also showed an increase in autoimmune hypopigmentation. 22 Together, these data indicate that treatment with agonistic anti-GITR, alone or as an adjunct to active immunization, increases the ability to break immune tolerance.…”