Skin homing of Sézary cells involves SDF-1-CXCR4 signaling and down-regulation of CD26/dipeptidylpeptidase IV.
Sézary syndrome (SS) is a rare form of cutaneous T-cell lymphoma (CTCL) characterized by a distinct metastatic pattern mainly involving blood and skin. Chemokines and their receptors play a critical role in cellular recruitment and homing to tissues and in the metastatic process of several tumors including non-Hodgkin T-cell lymphomas (NHLs). Here we report that SS cells express a functionally active CXCR4 and that its ligand SDF-1 is abundantly produced in the skin, which represents the main destination of SS cell spreading. SDF-1 is normally inactivated by proteolytic cleavage by the CD26/dipeptidylpeptidase IV (DPPIV). The lack of CD26 from the cell surface is a hallmark of circulating SS cells. We also show that the CD26(-) phenotype is maintained also in skin-infiltrating neoplastic T lymphocytes and that SS-affected individuals exhibit a reduced activity of plasma soluble CD26. Finally, we observe that the addition of soluble CD26 reduces the migratory response of SS cells to SDF-1 whereas the inhibition of the CD26 peptidase activity in Hut78, a CD26(+) CTCL cell line, enhances the SDF-1-induced migration of these cells. Our findings suggest that the SDF-1-CXCR4 axis could play an important role in skin homing of SS through the regulatory activity of CD26.
Narducci
Maria Grazia
MG
Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Laboratorio di Oncologia Molecolare, III e V Divisione Dermatologica, Laboratorio di Immunologia e Laboratorio di Patologia Vascolare, Via dei Monti di Creta, Rome, Italy. narducci@idi.it
Scala
Enrico
E
Bresin
Antonella
A
Caprini
Elisabetta
E
Picchio
Maria Cristina
MC
Remotti
Daniele
D
Ragone
Gianluca
G
Nasorri
Francesca
F
Frontani
Marina
M
Arcelli
Diego
D
Volinia
Stefano
S
Lombardo
Giuseppe Alfonso
GA
Baliva
Giannandrea
G
Napolitano
Monica
M
Russo
Giandomenico
G
D000243:Adenosine Deaminase / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D009362:Neoplasm Metastasis; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012751:Sezary Syndrome / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D006023:Glycoproteins; D019718:Receptors, CXCR4; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase