CXCL13 Is Highly Produced by Sézary Cells and Enhances Their Migratory Ability via a Synergistic Mechanism Involving CCL19 and CCL21 Chemokines

Abstract

Chemokine and chemokine receptors expressed by normal and neoplastic lymphocytes play a key role in cell recruitment into skin and lymph nodes. The aim of this study was to get further insights into the role of chemokines in pathogenesis and progression of cutaneous T-cell lymphoma (CTCL) with particular regard to Sézary Syndrome (SS), a CTCL variant with blood involvement. Here, we show that functional CXCL13 homeostatic chemokine is strongly up-regulated in SS cells, well-detectable in skin lesions and lymph nodes, and measurable at high concentration in plasma of SS patients, at different levels during disease progression. Furthermore, we show that the addition of CXCL13 to CCL19 or to CCL21, the selective CCR7 agonists responsible for lymph node homing, strongly enhances the migration of CCR7+ SS cells. We also show that neutralization of the CCR7 receptor strongly impairs CCL19/21-induced chemotaxis of SS cells both in the absence or presence of CXCL13. Additional experiments performed to investigate the survival, adhesion, and metalloproteases secretion indicate that CXCL13 combined with CCL19 and CCL21 mainly affects the chemotaxis of SS cells. Our findings suggest that this newly described CXCL13 expression in SS represents a new pathogenetic mechanism of diagnostic significance. [Cancer Res 2008;68(17):7137-46]

Follicular center helper T-cell (TFH) marker positive mycosis fungoides/Sezary syndrome

“…They did not detect expression of CXCL-13 in three skin biopsies involved by mycosis fungoides in their study. 42 CXCL-13 immunoreactivity was encountered infrequently (2 of 14 (14%)) in mycosis fungoides cutaneous lesions studied by Picchio et al 54 However, these authors noted that CXCL-13 was commonly expressed in Sezary syndrome samples (13 of 16, 81%)). The increase frequency of expression of CXCL-13 between Sezary syndrome and mycosis fungoides observed by these authors was similar to the increased frequency of PD-1 expression on Sezay syndrome cells compared with mycosis fungoides cells noted by Wada et al 52 Although we did not evaluate expression of follicular center helper T-cell markers by mycosis fungoides stage, it is interesting to note that circulating lymphoma cells were detected all (6/6) patients in which blood was evaluated.…”

Comprehensive analysis of PTEN status in Sézary syndrome

“…Consistent with this hypothesis, we found AKT activation in SS cells that infiltrate the skin but not in the circulating ones, suggesting that skin microenvironment stimulates SS cells through direct-cell interactions and/or growth factor stimulation. A hypothesis, that PTEN reduction can amplify pathways induced by SS cell adhesion to the cutaneous milieu, thus promoting growth/survival of skin-infiltrating malignant lymphocytes, is supported by various findings: first, in the skin, SS cells interact with Langerhans cells in the intraepidermal Pautrier microabscess; second, SS cells coexpress skin homing receptors as CLA and CCR4 that specifically bind adhesion molecules present on endothelial cells of the skin, such as E-selectin and TARC 36 ; and third, SS cells that migrate via chemokines, 20,37 induce PI3K pathway, leading to AKT activation. 38 The SS genome is characterized by a high chromosomal instability with recurrent gains, losses, or rearrangements.…”

Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery

“…As we understand more about allosteric ligands, it is likely that they, too, will be discovered to stabilize a variety of conformations, ranging from the "full on" conformation (which may be typical of a full allosteric agonist), to "variant partially on" conformations (which may be typical of biased agonists or allosteric modulators), and to "off" conformations (which may be typical of allosteric inhibitors). It is particularly interesting that there are examples where even natural ligands might express differential functional profiles at a naturally occurring receptor (Picchio et al, 2008;Moxley et al, 2009) (see section V.C.2.c), as was first described for CCL19/CCL21 at the CCR7 receptor (Kohout et al, 2004). Although the specific structural basis for this is not yet clear, it is consistent with the notion that these ligands stabilize distinct active conformations that facilitate different patterns of proximal effector interactions.…”