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Immune impairments in multiple myeloma bone marrow mesenchymal stromal cells

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Abstract

In multiple myeloma (MM), bone marrow mesenchymal stromal cells (BM-MSCs) play an important role in pathogenesis and disease progression by supporting myeloma cell growth and immune escape. Previous studies have suggested that direct and indirect interactions between malignant cells and BM-MSCs result in constitutive abnormal immunomodulatory capacities in MM BM-MSCs. The aim of this study was to investigate the mechanisms that underlie these MM BM-MSCs abnormalities. We demonstrated that MM BM-MSCs exhibit abnormal expression of CD40/40L, VCAM1, ICAM-1, LFA-3, HO-1, HLA-DR and HLA-ABC. Furthermore, an overproduction of IL-6 (1,806 ± 152.5 vs 719.6 ± 18.22 ng/mL; p = 0.035) and a reduced secretion of IL-10 (136 ± 15.02 vs 346.4 ± 35.32 ng/mL; p = 0.015) were quantified in culture medium when MM BM-MSCs were co-cultured with T lymphocytes compared to co-cultures with healthy donor (HD) BM-MSCs. An increased Th17/Treg ratio was observed when T cells were co-cultured with MM BM-MSCs compared to co-cultures with HD BM-MSCs (0.955 vs 0.055). Together, these observations demonstrated that altered immunomodulation capacities of MM BM-MSCs were linked to variations in their immunogenicity and secretion profile. These alterations lead not only to a reduced inhibition of T cell proliferation but also to a shift in the Th17/Treg balance. We identified factors that are potentially responsible for these alterations, such as IL-6, VCAM-1 and CD40, which could also be associated with MM pathogenesis and progression.

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Abbreviations

BM:

Bone marrow

BrdU:

5-Bromo-2-deoxy-uridine

CCL5:

Chemokine (C–C motif) ligand 5

CFSE:

Carboxyfluorescein succinimidyl ester

CM:

Conditioned medium

ELISA:

Enzyme-linked immunosorbent assay

FOXP3:

Forkhead box P3

HD:

Healthy donors

HGF:

Hepatocyte growth factor

HLA:

Human leukocyte antigen

HO-1:

Hemeoxygenase-1

ICAM-1:

Intercellular adhesion molecule-1

IFN:

Interferon

IL:

Interleukin

IL-23R:

Interleukin-23 receptor

LFA-3:

Lymphocyte function-associated antigen-3

MCP-1:

Monocyte chemotactic protein-1

MIP-1α:

Macrophage inflammatory protein-1 alpha

MLR:

Mixed lymphocyte reactions

MM:

Multiple myeloma

MMP:

Matrix metalloproteinase

MSC:

Mesenchymal stromal cell

PBMC:

Peripheral blood mononuclear cells

PCs:

Plasma cells

PGE2:

Prostaglandin E2

PHA:

Phytohemagglutinin

RORγt:

RAR-related orphan receptor gamma t

SEM:

Standard error of the mean

TGF:

Tumor growth factor

Th:

T helper cells

TNF:

Tumor necrosis factor

Treg:

T regulatory cells

VCAM-1:

Vascular cell adhesion molecule-1

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Acknowledgments

This work was supported by a Grant provided by the “Fonds de la Recherche Scientifique—Fonds National de la Recherche Scientifique” (FRS-FNRS of Belgium—Grant-Télévie FC79946) and by a fund Granted by “Les Amis de l’Institut Bordet.”

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Laboratory of Clinical Cell Therapy, Institut Jules Bordet - Université Libre de Bruxelles (ULB), 808, Route de Lennik, 1070, Brussels, Belgium

    Thibaud André, Mehdi Najar, Basile Stamatopoulos, Karlien Pieters & Laurence Lagneaux

  2. Hematology Department, Institut Jules Bordet, Brussels, Belgium

    Dominique Bron & Nathalie Meuleman

  3. Laboratory of Hematology, Erasmus Hospital, Brussels, Belgium

    Olivier Pradier

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  1. Thibaud André
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  2. Mehdi Najar
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  3. Basile Stamatopoulos
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  4. Karlien Pieters
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  5. Olivier Pradier
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  6. Dominique Bron
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  7. Nathalie Meuleman
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  8. Laurence Lagneaux
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Correspondence to Thibaud André.

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Thibaud André and Mehdi Najar have contributed equally to this work.

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André, T., Najar, M., Stamatopoulos, B. et al. Immune impairments in multiple myeloma bone marrow mesenchymal stromal cells. Cancer Immunol Immunother 64, 213–224 (2015). https://doi.org/10.1007/s00262-014-1623-y

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