Funding sources This work was supported by grants-in-aid for Scientific Research and for Specially Promoted Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan. M.O. is currently supported by a Human Frontier Science Program Long-Term Fellowship.
Perturbations of both nonregulatory and regulatory FOXP3+ T cells in patients with malignant melanoma
Article first published online: 5 APR 2011
© 2011 The Authors. BJD © 2011 British Association of Dermatologists
British Journal of Dermatology
Volume 164, Issue 5, pages 1052–1060, May 2011
How to Cite
Fujii, H., Arakawa, A., Kitoh, A., Miyara, M., Kato, M., Kore-eda, S., Sakaguchi, S., Miyachi, Y., Tanioka, M. and Ono, M. (2011), Perturbations of both nonregulatory and regulatory FOXP3+ T cells in patients with malignant melanoma. British Journal of Dermatology, 164: 1052–1060. doi: 10.1111/j.1365-2133.2010.10199.x
Conflicts of interest None declared.
- Issue published online: 26 APR 2011
- Article first published online: 5 APR 2011
- Accepted manuscript online: 27 DEC 2010 02:25AM EST
- Accepted for publication 21 December 2010
Background ‘FOXP3+ regulatory T cells’ (Tregs) are reported to be increased in tumour-bearing hosts including patients with melanoma, leading to tumour immune suppression. However, this idea is challenged by recent evidence that the ‘FOXP3+ Treg’ fraction in fact contains activated ‘nonregulatory’ T cells. Also, FOXP3+ T cells are reported to have functionally and kinetically distinct subsets.
Objectives To investigate whether either or both of regulatory and ‘nonregulatory’ FOXP3+ T cells are perturbed in patients with melanoma.
Methods FOXP3+ T cells were classified into three subsets, namely CD45RO+FOXP3low nonregulatory T cells, CD45RO+FOXP3high effector Tregs, and CD45RO−FOXP3low naïve Tregs, according to their expression levels of FOXP3 and CD45RO. The percentage and cytokine production of these FOXP3+ T-cell subsets were assessed by flow cytometry.
Results Both regulatory and nonregulatory T cells were increased in patients with melanoma. Moreover, we found three unexpected perturbations in FOXP3+ T-cell subsets: (i) patients with melanoma showed higher frequencies of FOXP3low nonregulatory T cells, which decreased and normalized after tumour removal; (ii) FOXP3low naïve Tregs containing higher frequencies of interferon-γ+ cells increased with tumour progression; and (iii) CD45RO+FOXP3high effector Tregs were pronouncedly infiltrated around tumour tissues.
Conclusions These findings demonstrate that patients with melanoma have distinct and differential perturbation of both regulatory and nonregulatory FOXP3+ T cells. The degree of perturbation is associated with tumour burden and progression, suggesting that the perturbation reflects fundamental pathophysiological processes in patients with melanoma. The presented analysis provides a practical approach to investigate the immunological environment of cancer patients.