Perturbations of both nonregulatory and regulatory FOXP3+ T cells in patients with malignant melanoma

Authors

  • H. Fujii,

    1. Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo Kyoto 606-8507, Japan
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  • A. Arakawa,

    1. Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo Kyoto 606-8507, Japan
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  • A. Kitoh,

    1. Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo Kyoto 606-8507, Japan
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  • M. Miyara,

    1. Laboratoire d’Immunochimie
    2. Department of Internal Medicine 2
    3. Laboratoire d’Immunologie Tissulaire et Cellulaire (INSERM UMR-S945), Hôpital Pitié Salpêtrière, Paris, France
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  • M. Kato,

    1. Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo Kyoto 606-8507, Japan
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  • S. Kore-eda,

    1. Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo Kyoto 606-8507, Japan
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  • S. Sakaguchi,

    1. Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    2. WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
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  • Y. Miyachi,

    1. Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo Kyoto 606-8507, Japan
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  • M. Tanioka,

    1. Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo Kyoto 606-8507, Japan
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  • M. Ono

    1. Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo Kyoto 606-8507, Japan
    2. Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
    3. WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
    4. Immunobiology Unit, Institute for Child Health, University College London, London WC1N 1EH, U.K.
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  • 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.

  • Conflicts of interest
    None declared.

Akiko Arakawa and Masahiro Ono.
E-mail: arakawa@kuhp.kyoto-u.ac.jp and m.ono@ich.ucl.ac.uk

Summary

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.

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