The Role of Regulatory T Cells and TH17 Cells in Multiple Myeloma

Abstract

The development of multiple myeloma (MM) involves a series of genetic alterations and changes in the bone marrow microenvironment, favoring the growth of the tumor and failure of local immune control. Quantitative and functional alterations in CD4+ and CD8+ T cells have been described in MM. The balance between T regulatory cells (Treg) and T helper (Th) 17 cells represents one essential prerequisite for maintaining anti-tumor immunity in MM. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against infections and tumor cells. In MM patients, Tregs seem to contribute to myeloma-related immune dysfunction and targeting them could, therefore, help to restore and enhance vital immune responses. Th17 cells protect against fungal and parasitic infections and participate in inflammatory reactions and autoimmunity. The interplay of TGF-β and IL-6, expressed at high levels in the bone marrow of myeloma patients, may affect generation of Th17 cells both directly or via other pro-inflammatory cytokines and thereby modulate antitumor immune responses. A detailed analysis of the balance between Tregs and Th17 cells seems necessary in order to design more effective and less toxic modes of immunotherapy myeloma which still is an uncurable malignancy.

Impact of post-ASCT maintenance therapy on outcomes in patients with newly diagnosed multiple myeloma in Connect MM

“…1, 2 The standard of care for eligible patients with newly diagnosed MM (NDMM) is autologous stem cell transplantation (ASCT) followed by lenalidomide maintenance.…”

Non-redundant roles for Th17 and Th22 cells in multiple myeloma clinical correlates

“…T regulatory cells (Tregs) are often studied in relation to Th17 cells, as their differentiation is mutually controlled, and the Treg/Th17 balance is considered to be a marker of immunoregulatory function. 10 A skew towards an increase of the Treg/Th17 cell ratio in MM has been associated with an immunosuppressive state 26,27 and, accordingly, long-term survival in MM has been correlated with a favorable Treg/Th17 balance. 26,28 …”

WT1-specific T-cell responses in high-risk multiple myeloma patients undergoing allogeneic T cell–depleted hematopoietic stem cell transplantation and donor lymphocyte infusions

“…Preliminary results from our laboratory show a general trend toward increasing PB and BM Treg frequencies with worsening disease status, concordant with recent findings that increased Treg frequencies in MM patients are associated with a reduced overall survival. [44][45][46] More recently, Th17 cells have been shown to play an immunomodulatory role in the pathogenesis of MM, by promoting the outgrowth of MM cells while inhibiting immune function. 47 The administration of chemotherapy may eliminate populations of immunosuppressive cells such as Treg, MDSC, and Th17 cells, while promoting the generation and cross-presentation of MM-derived WT1 peptides, and enhancing the sensitization of incoming donor lymphocytes against those WT1 peptides.…”