Human regulatory T cells suppress proliferation of B lymphoma cells

Abstract

Activated regulatory T cells (Tregs) suppress proliferation and differentiation of normal B cells. In our study, allogeneic polyclonal CD4 (+) CD25 (+) Tregs and CD4 (+) CD25 (+) CD127(lo)Tregs expanded in vitro in the presence of rapamycin and low dose IL-2 suppressed proliferation of 11 out of 12 established lymphoma B-cell lines. The effect of expanded CD4 (+) CD25 (+) Tregs on survival of freshly isolated lymphoma B cells maintained in culture with soluble multimeric CD40L and IL-4 was variable across lymphoma entities. The survival of freshly isolated follicular lymphoma cells usually decreased in cocultures with CD4 (+) CD25 (+) Tregs. Treg effect on chronic lymphocytic leukemia/small lymphocytic lymphoma cells ranged from suppression to help in individual patients. CD4 (+) CD25 (+) Tregs or CD4 (+) CD25 (+) CD127(lo)Tregs expanded ex vivo with rapamycin could be used to suppress regrowth of residual lymphoma after autologous hematopoietic cell transplantation (HCT), and to counteract both graft-versus-host disease and lymphoma re-growth after allogeneic HCT in select patients with lymphoma susceptible to the regulation by Tregs.

The emerging role of anti‐CD25 directed therapies as both immune modulators and targeted agents in cancer

“…This may be explained by these infiltrating Tregs suppressing the activation of tumour antigen-specific effector T cells as well as hindering the differentiation and activation of normal and lymphoma B cells (Nishikawa & Sakaguchi, 2014;Grygorowicz et al, 2016) Consequences of this may be illustrated in a study in follicular lymphoma which showed an association of follicular localisation of Tregs with poor survival (Farinha et al, 2010). This may be explained by these infiltrating Tregs suppressing the activation of tumour antigen-specific effector T cells as well as hindering the differentiation and activation of normal and lymphoma B cells (Nishikawa & Sakaguchi, 2014;Grygorowicz et al, 2016) Consequences of this may be illustrated in a study in follicular lymphoma which showed an association of follicular localisation of Tregs with poor survival (Farinha et al, 2010).…”

“…Many tumours contain significant numbers of Tregs and, in particular, those that demonstrate a higher ratio of CD4 + CD25 + FOXP3 + Tregs to CD8 + cytotoxic T cells are thought to predict for a poorer prognosis. This may be explained by these infiltrating Tregs suppressing the activation of tumour antigen-specific effector T cells as well as hindering the differentiation and activation of normal and lymphoma B cells (Nishikawa & Sakaguchi, 2014;Grygorowicz et al, 2016) Consequences of this may be illustrated in a study in follicular lymphoma which showed an association of follicular localisation of Tregs with poor survival (Farinha et al, 2010). In this study with median follow-up of 17Á1 years, FOXP3 upregulation was used as a marker of Treg infiltration and follicular localisation of FOXP3 + cells significantly improved prediction of transformation risk over and above the survival prognostication provided by the established Internal Prognostic Index.…”

“…In this study with median follow-up of 17Á1 years, FOXP3 upregulation was used as a marker of Treg infiltration and follicular localisation of FOXP3 + cells significantly improved prediction of transformation risk over and above the survival prognostication provided by the established Internal Prognostic Index. There is, however, conflicting evidence on the prognostic significance of Tregs in malignancy (Grygorowicz et al, 2016). Infiltrating Tregs correlated with improved survival in studies of patients with follicular lymphoma (Lee et al, 2008;Tzankov et al, 2008), both germinal centre and non-germinal centre subtypes of diffuse large B cell lymphoma (DLBCL) (Lee et al, 2008;Tzankov et al, 2008) and Hodgkin lymphoma (HL) (Alvaro et al, 2005;Tzankov et al, 2008).…”

Cell-Based Therapies with T Regulatory Cells

“…It is possible that Tregs traffic to the tissues and appropriate clones guard Tconvs from GvHD [65]. At the same time, some Treg clones might control proliferation of residual tumor cells facilitating GvL executed by Tconvs [66]. If true, the dependency of efficacy on particular clones highlights the need for antigen-specific Treg preparations.…”

Expanding Diversity and Common Goal of Regulatory T and B Cells. II: In Allergy, Malignancy, and Transplantation

“…The main function of Tregs is to inhibit T effector cells: CD4 + and CD8 + lymphocytes, dendritic cells (DCs), and natural killer (NK) cells in the site of immune response (Chaput et al 2007 ; Orentas et al 2006 ; Woo et al 2002 ). In contrast to solid tumors, the role of Tregs in lymphoproliferative disorders is opposite—the simplified explanation is that these cells suppress proliferating B cells (Grygorowicz et al 2016 ).…”