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IL-10 inducible CD8+ regulatory T-cells are enriched in patients with multiple myeloma and impact the generation of antigen-specific T-cells

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Abstract

Tumor-mediated immunosuppression via regulatory T-cells is a key player among the various immune-escape mechanisms in multiple myeloma. We analyzed the generation, distribution, function and immunophenotype of CD8+CD28− regulatory T-cells in patients with multiple myeloma. Functionality of CD8+CD28− T-cells was assessed by immunological assays using ex vivo generated antigen-specific T-cells from patients with plasma cell dyscrasias and healthy donors. Detailed analysis of distribution, immunophenotype and cytotoxic potential of CD8+CD28− T-cells was performed by flow cytometry and ELISA. We found that the amount of CD8+CD28− T-cells was directly correlated with the suppression of antigen-specific T-cell responses in patients with plasma cell dyscrasia. Analyzing the CD8+CD28− T-cells in detail, increased numbers of these cells were observed in the bone marrow (i.e., tumor microenvironment) of patients with plasma cell dyscrasia. Furthermore, we identified the expression of lymphocyte function-associated antigen 1 (LFA-1) as a marker of immunosuppression and defined the CD8+CD28−CD57+LFA-1high population as the relevant immunosuppressive compartment. These regulatory T-cells act as immunosuppressors via soluble factors and incubation with IL-10 augmented their immunosuppressive capacity. The immunosuppressive regulatory network of IL-10 and the CD8+CD28−CD57+LFA-1high regulatory T-cells show unique characteristics and contribute to the tumor immune escape mechanism in patients with multiple myeloma.

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Abbreviations

APD:

Advanced plasma-cell disease

EPD:

Early plasma-cell disease

HD:

Healthy donor

LFA-1:

Lymphocyte function-associated antigen 1

MGUS:

Monoclonal gammopathy of undetermined significance

MM:

Multiple myeloma

MNC:

Mononuclear cells

PB:

Peripheral blood

PCD:

Plasma cell dyscrasia

SLE:

Systemic lupus erythematosus

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Author notes

  1. Julian Plaumann and Melanie Engelhardt contributed equally to this paper.

Authors and Affiliations

  1. Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany

    Julian Plaumann, Melanie Engelhardt, Mohamed H. S. Awwad, Marc S. Raab, Jens Hillengass, Brigitte Neuber, Carsten Müller-Tidow, Hartmut Goldschmidt & Michael Hundemer

  2. Department of Hematology, Oncology and Pneumology, University Medical Center (UMC) of the Johannes Gutenberg University Mainz, Mainz, Germany

    Hakim Echchannaoui & Eva Amman

  3. National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany

    Niels Halama & Hartmut Goldschmidt

Authors
  1. Julian Plaumann
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Contributions

Study conception and design: Julian Plaumann, Melanie Engelhardt, Michael Hundemer. Acquisition of data: Julian Plaumann, Melanie Engelhardt, Brigitte Neuber, Eva Amman. Analysis and interpretation of data: Julian Plaumann, Melanie Engelhardt, Eva Amman, Hakim Echchannaoui, Mohamed H. S. Awwad, Michael Hundemer. Drafting of manuscript: Julian Plaumann, Michael Hundemer. Critical revision: Mohamed H. S. Awwad, Marc S. Raab, Jens Hillengass, Niels Halama, Carsten Müller-Tidow, Hartmut Goldschmidt.

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Correspondence to Michael Hundemer.

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All human studies were performed after obtaining written informed consent in accordance with the Declaration of Helsinki and were approved by the ethics committee of the Medical Faculty, University of Heidelberg according to the institutional guidelines. Data safety management was performed according to the data safety regulations of the University Hospital Heidelberg.

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Informed consent was obtained from all individual participants included in the study.

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Plaumann, J., Engelhardt, M., Awwad, M.H.S. et al. IL-10 inducible CD8+ regulatory T-cells are enriched in patients with multiple myeloma and impact the generation of antigen-specific T-cells. Cancer Immunol Immunother 67, 1695–1707 (2018). https://doi.org/10.1007/s00262-018-2230-0

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