Molecular characterization of subcutaneous panniculitis-like T-cell lymphoma reveals upregulation of immunosuppression- and autoimmunity-associated genes.
BACKGROUND
Subcutaneous panniculitis-like T cell lymphomas represent a rare and difficult to diagnose entity of cutaneous T cell lymphomas. SPTL affects predominantly young adults and presents with multifocal subcutaneous nodules and frequently associated autoimmune features. The pathogenesis of SPTL is not completely understood.


METHODS
The aim of this study was to unravel molecular pathways critical to the SPTL pathogenesis. Therefore, we analyzed 23 skin samples from 20 newly diagnosed SPTL patients and relevant control samples of adipose and non-malignant panniculitis tissue by using gene expression microarray, quantitative PCR, and two-colour immunohistochemistry.


RESULTS
Interestingly, indoleamine 2,3-dioxygenase (IDO-1), an immunotolerance-inducing enzyme, was among the most highly overexpressed genes in all comparisons. The expression of Th1-specific cytokines, known to be associated with autoimmune inflammation (i.e. IFNG, CXCR3, CXCL9, CXCL10, CXCL11, and CCL5), were also significantly increased. Confirmed using immunohistochemistry, the morphologically malignant lymphocytes expressed CXCR3 and CXCL9. IDO-1 expression was found both in some morphologically malignant lymphocytes rimming the adipocytes and in surrounding CD11c(-) CD68(-) cells but not in CD11c(+) dendritic cells in the microenvironment. The proportion of FoxP3+ cells in SPTL exceeded that in the benign panniculitis samples.


CONCLUSIONS
Our results indicate that the up regulation of the tolerogenic IDO-1 together with the up regulation of IFNG, CXCR3 ligands, and CCL5 are features of SPTL lesions. We anticipate that the IFNG-inducible IDO-1 expression contributes to the formation of an immunosuppressive microenvironment, favorable for the malignant T cells. This study provides a relevant molecular basis for further studies exploring novel therapeutic means for subcutaneous T cell lymphoma.
Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. pilvi.maliniemi@helsinki.fi.
Pilvi
P
Maliniemi
Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. sonja.hahtola@helsinki.fi.
Sonja
S
Hahtola
Systems Biology Laboratory, Institute of Biomedicine and Genome-Scale Biology Program, University of Helsinki, Helsinki, Finland. kristian.ovaska@helsinki.fi.
Kristian
K
Ovaska
Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. leila.jeskanen@hus.fi.
Leila
L
Jeskanen
Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. liisa.vakeva@hus.fi.
Liisa
L
Väkevä
Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. kirsi.niiranen@helsinki.fi.
Kirsi
K
Jäntti
Johannes-Wesling-Klinikum Minden, Akademisches Lehrkrankenhaus der Medizinischen Hochschule Hannover, Minden, Germany. Rudolf.Stadler@muehlenkreiskliniken.de.
Rudolf
R
Stadler
Institut Pasteur, Département d'immunologie, Equipe Dynamique des réponses immunes, 25 rue du Docteur Roux, 75015, Paris, France. david.michonneau@pasteur.fr.
David
D
Michonneau
Service d'anatomie et de cytologie pathologiques, Hôpital Necker-Enfants-Malades, AP-HP, 149, rue de Sèvres, 75743, Paris Cedex 15, France. sylvie.fraitag@nck.aphp.fr.
Sylvie
S
Fraitag
Systems Biology Laboratory, Institute of Biomedicine and Genome-Scale Biology Program, University of Helsinki, Helsinki, Finland. sampsa.hautaniemi@helsinki.fi.
Sampsa
S
Hautaniemi
Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. annamari.ranki@hus.fi.
Annamari
A
Ranki
D000293:Adolescent; D000328:Adult; D000368:Aged; D015551:Autoimmunity / Q000235:genetics*; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D015434:Panniculitis / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics*; D055815:Young Adult
C499707:CXCL3 protein, human; C080810:CXCL9 protein, human; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D016207:Cytokines; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase