Abstract
Hodgkin lymphoma (HL) is characterized by the presence of a small number of tumor cells in a rich background of inflammatory cells, but the contribution of the abundant nontumor cells to HL pathogenesis is poorly understood. We showed that migratory CD4(+) cells induced by HL cells were hyporesponsive to T-cell receptor stimulation and suppressed the activation/proliferation of the effector CD4(+) T cells in an autologous setting. We further showed that HL cells in the affected lymph nodes were surrounded by a large number of lymphocytes expressing both CC chemokine receptor 4 (CCR4) and FOXP3. These findings indicate that the migratory cells induced by HL cells function as regulatory T (Treg) cells so that these cells create a favorable environment for the tumor cells to escape from host immune system. In addition, we showed that a chimeric anti-CCR4 monoclonal antibody (mAb) could deplete CCR4(+) T cells and inhibit the migration of CD4(+)CD25(+) T cells in vitro. Recognition of the importance of CCR4(+) Treg cells in the pathogenesis of HL will allow rational design of more effective treatments, such as use of an anti-CCR4 mAb, to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.
Highlights
Hodgkin lymphoma (HL) is characterized by the presence of a small number of tumor cells in a rich background of T and B cells, macrophages, and other inflammatory cells [1]
We showed here that HL cell lines attracted CD4+CD25+chemokine receptor 4 (CCR4)+ T cells, but CD8+ T cells and anaplastic large cell lymphoma (ALCL) cell lines attracted neither CD4+CD25+CCR4+ T cells nor CD8+ T cells. Most importantly, this is the first report showing that migratory cells, induced by the supernatants of HL tumor cells, are hyporesponsive to T-cell receptor (TCR) stimulation and suppress the activation/proliferation of the effector T cells in an autologous setting. These findings show that the migratory cells induced by HL cells function as Treg cells so that these cells create a favorable environment for the tumor cells to escape from host immune system
We showed here that rh-TARC/CCL17 and rh-MDC/CCL22 exhibited robust chemotactic activity for CD4+CD25+CCR4+ cells and that the migratory cells induced by these two specific ligands for CCR4 were hyporesponsive to TCR stimulation and suppressed the activation/proliferation of the effector T cells in an autologous setting
Summary
Hodgkin lymphoma (HL) is characterized by the presence of a small number of tumor cells in a rich background of T and B cells, macrophages, and other inflammatory cells [1]. The contribution of these abundant nontumor cells to the pathogenesis of HL is still poorly understood. CCL17 and MDC/CCL22, is expressed on regulatory T (Treg) cells [5,6,7] These observations prompted us to hypothesize that HL tumor cells produce TARC/CCL17 and/or MDC/CCL22 that mediate trafficking of CCR4-positive Treg cells to the tumor, and that this specific recruitment of Treg cells represents a mechanism by which the tumor might be capable of suppressing the host antitumor response. We examine the above hypothesis by using human peripheral blood mononuclear cells (PBMC) and HL cell lines in vitro, and we carry out double immunostaining with CCR4 and FOXP3, a hallmark of naturally occurring Treg cells [8,9,10,11], in affected lymph node tissues obtained from patients with HL
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