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Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and Sézary syndrome

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A Letter to the Editors to this article was published on 24 March 2018

Abstract

Tumor progression is associated with progressive immunosuppression mediated in part by T regulatory cell(s) (Treg) and/or myeloid-derived suppressor cell(s) (MDSC). Development of strategies to reduce populations of immune cells with suppressive function in cancer patients may enable the induction or recovery of immunity against tumor cells, which may limit or reverse disease progression. With a goal of developing Treg and MDSC neutralizing strategies to treat mycosis fungoides (MF) and Sézary syndrome (SzS), we determined the association between disease stage and suppressor cell populations in patients with MF/SzS, including those responding to therapy. We found elevations in Treg populations, across Treg subtypes, in patients with SzS, and these Treg markedly suppressed proliferation of autologous CD4+CD25− responder T cells. Interestingly, while MDSC numbers were not increased in MF/SzS patients, MDSC from patients with stage IB and above produced significantly more reactive oxygen species than those from stage IA MF patients and control cohorts. Therapy with the CD25-targeting agent denileukin diftitox or IFN-α2b was associated with a reduction in Treg numbers or MDSC function, respectively. These studies identify potential mechanisms of action for these therapies and support the development of coordinated strategies targeting both Treg and MDSC activities in patients with MF/SzS.

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Abbreviations

ARGI:

Arginase-I

DD:

Denileukin diftitox

IFN:

Interferon

MDSC:

Myeloid-derived suppressor cell(s)

MF:

Mycosis fungoides

nTreg:

Naturally occurring T regulatory cells, CD4+CD25+Foxp3+ cells

PEG:

Polyethylene glycol (PEG)ylated

ROS:

Reactive oxygen species

SzS:

Sézary syndrome

Th3 cells:

T helper 3 cells, CD4+CD25−Foxp3+ cells

Tr1 cells:

T regulatory 1 cells, CD4+CD25−CTLA4+ cells

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Acknowledgements

The authors would like to thank Sean M. Alber (University of Pittsburgh Department of Cell Biology) for assisting with images capture and analysis, Laura Strauss and Mary Jo Buffo for technical assistance with Treg functionality assay. We thank Dan Ilkovitch, MD, Ph.D. for the critical reading of the manuscript. We would like to thank the patients who volunteered their time and made this effort possible.

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Authors and Affiliations

  1. Department of Dermatology, University of Pittsburgh, Suite 500.68 Medical Arts Building, 3708 Fifth Avenue, Pittsburgh, PA, 15213, USA

    Larisa J. Geskin, Oleg E. Akilov, Soonyou Kwon, Michael Schowalter & Louis D. Falo Jr.

  2. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Simon Watkins & Lisa H. Butterfield

  3. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

    Theresa L. Whiteside

  4. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Lisa H. Butterfield

  5. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    Louis D. Falo Jr.

  6. Center for Biological Imaging, University of Pittsburgh, Pittsburgh, PA, USA

    Simon Watkins

  7. UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Larisa J. Geskin, Theresa L. Whiteside, Lisa H. Butterfield & Louis D. Falo Jr.

  8. Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, USA

    Louis D. Falo Jr.

  9. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Louis D. Falo Jr.

  10. Department of Dermatology, Columbia University, New York, NY, USA

    Larisa J. Geskin

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  1. Larisa J. Geskin
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Correspondence to Louis D. Falo Jr..

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Funding

This work was supported by Research Center Grants for Specialized Programs of Research of Excellence (P50CA121973) of National Institute of Health, Clinical and Translational Science and M01 Award of National Center for Research Resources.

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The authors declare that they have no conflict of interest.

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Geskin, L.J., Akilov, O.E., Kwon, S. et al. Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and Sézary syndrome. Cancer Immunol Immunother 67, 423–434 (2018). https://doi.org/10.1007/s00262-017-2090-z

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