CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs.
Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population that shares certain characteristics including an aberrant myeloid phenotype and the ability to suppress T cells. MDSCs have been predominantly studied in malignant diseases and findings suggest involvement in tumor-associated immune suppression. Chronic lymphocytic leukemia (CLL) is the leukemia with the highest incidence among adults. Immune defects occur already at early disease stages and impact the clinical course. We assessed presence, frequency, association to other immune parameters, and functional properties of circulating CD14(+) cells lacking HLA-DR expression (HLA-DR(lo)) in patients with untreated CLL. These monocytic cells represent one of the best-defined human MDSC subsets. Frequency of CD14(+)HLA-DR(lo) cells was significantly increased in CLL patients. Furthermore, MDSCs suppressed in vitro T-cell activation and induced suppressive regulatory T cells (TRegs). The MDSC-mediated modulation of T cells could be attributed to their increased indoleamine 2,3-dioxygenase (IDO) activity. CLL cells induced IDO(hi) MDSCs from healthy donor monocytes suggesting bidirectional crosstalk between CLL-cells, MDSCs, and TRegs. Overall, we identified a MDSC population that expands in CLL. The exact mechanisms responsible for such accumulation remain to be elucidated and it will be of interest to test whether antagonizing suppressive functions of CLL MDSCs could represent a mean for enhancing immune responses.
Department of Internal Medicine 5, Hematology and Oncology, and.
Regina
R
Jitschin
Department of Internal Medicine 5, Hematology and Oncology, and.
Martina
M
Braun
Institute of Pathology, Department of Nephropathology, University of Erlangen-Nuremberg, Erlangen, Germany;
Maike
M
Büttner
Institute of Functional Genomics, University of Regensburg, Regensburg, Germany;
Katja
K
Dettmer-Wilde
Department of Internal Medicine 5, Hematology and Oncology, and.
Juliane
J
Bricks
Department of Internal Medicine 5, Hematology and Oncology, and.
Jana
J
Berger
Onkologische Schwerpunktpraxis, Erlangen, Germany; and.
Michael J
MJ
Eckart
Department of Internal Medicine 5, Hematology and Oncology, and.
Stefan W
SW
Krause
Institute of Functional Genomics, University of Regensburg, Regensburg, Germany;
Peter J
PJ
Oefner
Department of Medicine, Hematology Centre, Karolinska University Hospital, Stockholm, Sweden.
Katarina
K
Le Blanc
Department of Internal Medicine 5, Hematology and Oncology, and.
Andreas
A
Mackensen
Department of Internal Medicine 5, Hematology and Oncology, and.
Dimitrios
D
Mougiakakos
D000328:Adult; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
D006684:HLA-DR Antigens; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018950:Lipopolysaccharide Receptors