Expression pattern of T-cell–associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma

Abstract

Chemokine receptors mediate the migration of lymphocytes through the binding of soluble ligands, and their expression is differentially regulated in lymphocyte subsets. The pattern of chemokine receptor expression in T-cell non-Hodgkin lymphoma has not been previously studied. Using a panel of mouse monoclonal antibodies, we studied the immunohistochemical expression of the Th1-associated chemokine receptor CXCR3 in 141 patients with T-cell lymphoma, and we studied the receptors CCR4 and CCR5 and some of their ligands in a subset of these tumors. Expression of CXCR3 was typical of the smaller T cells in angioimmunoblastic lymphoma (15 of 18 patients), angiocentric lymphoma (3 of 3 patients), histiocyte-rich tumors (4 of 5 patients), and unspecified T-cell lymphomas (17 of 39 patients). CXCR3 expression was seen in only 1 of 15 patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma. In contrast, all ALK-positive tumors showed diffuse reactivity for the Th2-associated receptor CCR4 (5 of 5 patients). CCR4 expression was also a consistent feature of the large-cell transformation of mycosis fungoides. CCR5 expression showed no consistent association with any T-cell tumor type. The chemokines Mig (CXCR3 ligand), TARC (CCR4 ligand), and MCP-2 (CCR5 ligand) were detected in intratumoral blood vessels and histiocytes. Mig was also coexpressed by a subset of CXCR3-positive tumor cells in 6 of 20 lymphomas. MCP-2 was highly expressed in stromal cells in 3 patients with nodal involvement by cutaneous T-cell lymphoma. As with normal T-cell subsets, we demonstrated that there is frequent differential expression of chemokine receptors in T-cell tumors, which may explain, in part, the distinctive patterns of spread in different tumor subtypes.

Circulating clonal CLA+ and CD4+ T cells in Sezary syndrome express the skin-homing chemokine receptors CCR4 and CCR10 as well as the lymph node-homing chemokine receptor CCR7

“…6 Furthermore, we confirm two recent reports and show that CCR4 is expressed on virtually all circulating CLA+ CD4+ T cells in patients with SS and MF. 7 Using specific TCR-Vb mAbs we directly demonstrated in four of our five patients with SS that a large number of circulating CLA+ CD4+ T cells expresses a single TCR-Vb chain which presumably represents the malignant clone. 19 Most importantly, we provide first evidence that most CLA+ CCR4+ CD4+ T cells of CTCL patients additionally express CCR10.…”

“…[3][4][5][6] It has recently been shown that malignant CLA+ CD4+ T cells in CTCL also express the skin-homing CC chemokine receptor CCR4. [7][8][9] Interaction between CCR4 and its ligand thymus and activation-regulated chemokine (TARC ⁄CCL17) on activated endothelial cells is important for T-cell extravasation by stimulating integrin-dependent adhesion of CLA+ T cells to intercellular adhesion molecule-1. 10 Interactions between the chemokine receptor CCR10 on T cells and the cutaneous T-cell attracting chemokine (CTACK ⁄CCL27) produced by activated keratinocytes which is also displayed on the dermal microvasculature are also critically involved in recruiting T cells to skin.…”

CCR4 as a novel molecular target for immunotherapy of cancer

“…Differential expression patterns of chemokine receptors in different T-cell lymphomas were reported for the first time in 2000 by Jones et al and this may explain, in part, the distinctive patterns of spread associated with each tumor subtype. (21) Subsequently, we carried out immunohistochemical analysis of CCR4 expression, evaluating 169 cases of T-cell and natural killer (NK)-cell lymphomas other than ATLL. CCR4 was rarely expressed in the three well-defined subtypes, namely, precursor T-lymphoblastic lymphoma, ALK-positive anaplastic large cell lymphoma (ALCL) and extranodal NK/T-cell lymphoma.…”

C‐C chemokine receptor 4 expression in CD8+ cutaneous T‐cell lymphomas and lymphoproliferative disorders, and its implications for diagnosis and treatment

“…19 Interactions between CCR4 and its ligands have been suggested to play an important pathogenic role in MF/SS, 14 and CCR4 expression has been reported to increase with advancing disease stage. [20][21][22] Kallinich et al 15 identified abundant expression of CCR4 on both tumour cells and reactive T cells in MF lesions. They found CCR4 to be highly expressed on the malignant cells in the patch/plaque and tumour stages of MF, whereas the proportion of CCR4-positive cells in reactive components of cellular infiltrates was lower in more advanced stages.…”