Constitutive Chemokine Receptor Expression in B-Cell Non-Hodgkin’s Lymphoma.

Chemokines are small peptides (∼8-14KDa) that play an essential role in both the innate and adaptive immune system. Chemokines are primarily involved in leukocyte trafficking, but are also involved in a number of cellular mechanisms. They elicit their effect through G-protein coupled receptors, the chemokine receptors (CKR). Functionally chemokines and their receptors are classified as inflammatory or constitutive. Constitutive CKRs and their ligands have a role in numerous diseases including malignancy, chronic inflammation and HIV infection. This study aimed to examine constitutive CKR expression in sub-types of B-cell NHL, of which there are limited studies so far. Lymph node preparations from patients with NHL were examined by flow cytometry using antibodies to CD20, CCR4, CCR6, CCR7, CCR9, CCR10, CXCR4 and CXCR5. The percentage of CD20 positive cells expressing the CKR under investigation was then calculated. The following cases were examined; follicular lymphoma (FL), n=11, Diffuse large B-cell lymphoma (DLBCL), n=11, mantle cell lymphoma (MCL) n=17, Burkitt’s lymphoma (BL), n=9 and MALT lymphoma, n=10. A number of differences between NHL sub-types were detected. FL cases generally had a lower expression of all the CKRs. CXCR5 and CXCR4 expression was high in all sub-types (>84% of B-cells) with no significant differences found, this would be expected as these CKRs are widely expressed in all B-cells. CCR10 expression was low or absent, with no significant differences detected. CCR6 and CCR9 show highest expression in MALT lymphomas, consistent with previous studies, but in comparison with other sub-types the differences was not significant. The most significant results were found with CCR7 and CCR4. CCR7 is expressed on naive T-cells, memory T-cells, B-cells and dendritic cells and is involved in the homing of lymphocytes to lymph nodes. CCR7 is currently the second most commonly reported CKR to be upregulated in malignancy, after CXCR4 and is related. We found very high levels of CCR7 in Mantle cell lymphoma (>90% of B-cells) as compared to other sub-types (p=0.005). CCR4 is expressed on Th2 and Treg lymphocytes, memory T cells and in a small subset of mature B-cells. CCR4 expression in T-cells has been correlated with an adverse prognosis in T-cell NHL and Hodgkin’s lymphoma, yet no systematic studies looking at CCR4 expression in B-cell neoplasms has been reported. These results showed a significant increase in CCR4 expression (>50% of B-cells) in DLBCL, MCL, MALT and BL as compared to FL (p<0.0001). We showed that there are differences in constitutive CKR expression in the different B-cell NHL types, with CCR4 expression being the most interesting finding. How CCR4 expression relates to prognosis in these lymphomas is as yet unknown but is under investigation. Targeting of the chemokine system using anti-CCR4 is already being used in clinical trials for T-cell neoplasms, and may be of potential benefit in selected B-cell neoplasms. Furthermore, the development of anti-CCR7 strategies may prove to be of benefit in the traditionally poor prognosis MCL patients.