There is accumulating evidence that naturally arising CD4+ regulatory T cells (TR cells), the majority of which constitutively express CD25, actively contribute to the maintenance of natural immunologic self-tolerance. Self-tolerance maintained by natural CD25+CD4+ TR cells may, however, impede development of tumor immunity by hampering the generation and activation of tumor-effector T cells recognizing autologous tumor cells. If this is the case, reduction of CD25+CD4+ TR cells or attenuation of their suppressive activity may enhance immune responses to autologous tumor cells.
We have examined whether the treatment of tumor-bearing mice with monoclonal antibodies (mAbs) specific for the molecules expressed by natural TR cells (e.g., CD25, CTLA-4, and GITR) can provoke or enhance tumor immunity through reduction of their number or suppressive activity. For example, administration of anti-GITR mAb (DTA-1), especially in combination with anti-CTLA-4 mAb, enhanced tumor immunity, leading to eradication of established tumors. Both mAbs not only abrogated in vitro TR cell-mediated suppression but also enhanced the activity of effector T cells in a synergistic manner. Manipulation of GITR-ligand can also enhance tumor immunity by a similar mechanism. In addition, our newly raised mAb that can differentiate natural TR cells from activated T cells in general provoked effective tumor immunity when administered to tumor-bearing animals.
In monitoring natural TR cells in the local tumor environment, the most specific molecular marker for TR cells at the moment is Foxp3, which is a forkhead/winged-helix transcription factor. Foxp3 is specifically expressed by CD25+CD4+ TR cells and appears to be a master control gene for their development and function. We show that monitoring of Foxp3+ T cells in tumor infiltrating T cells can be instrumental for assessing local tumor immunity.
This abstract was published in Cancer Immunity, a Cancer Research Institute journal that ceased publication in 2013 and is now provided online in association with Cancer Immunology Research.
- Copyright © 2005 by Shimon Sakaguchi