Cancer Immunity 5 Suppl 1:4 (2005)

Natural CD4+ regulatory T cells in tumor immunity

Shimon Sakaguchi^*, Tomoyuki Yamaguchi, Tomohisa Nishioka, Kwibeom Ko, Sayuri Yamazaki, Kyoko Nakamura, Keiji Hirota, and Takashi Nomura

Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
^*Presenting author

Abstract

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.

References

1. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22: 531-62. (PMID: 15032588) [PubMed]

2. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057-61. (PMID: 12522256) [PubMed]

3. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002; 3: 135-42. (PMID: 11812990) [PubMed]

4. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S. Dominant immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing CTLA-4. J Exp Med 2000; 192: 303-10. (PMID: 10899917) [PubMed]

5. Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999; 163: 5211-8. (PMID: 10553041) [PubMed]

6. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vitro administration of anti-CD25 (Interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999; 59: 3128-33. (PMID: 10397255) [PubMed]