|T cells are a key player in the control of multiple myeloma|
|It has been considered that NK cells play an important role during the anti-tumour responses against multiple myeloma (MM) cells, but the functions of T cells remain unclear. In this study published in the Journal of Clinical Investigation (here), Dr. Hill and colleagues determined the importance of T cells in MM control.
MM-bearing mice that had been treated with whole body irritation received T cell-depleted bone marrow or bone marrow, with or without T cell transfer. MM-bearing mice receiving bone marrow cells and T cells from tumour-naïve mice (referred to as BMT) had reduced tumour burden and elevated survival rates, compared to those receiving T cell-depleted bone marrow without T cell transfer (referred to as TCD-BMT). More importantly, MM-bearing mice receiving bone marrow cells and T cells from MM-experienced mice (referred to as BMT+) also showed improved outcome, which was not different to BMT. The above-observed treatment effects were CD4+ and CD8+ T cell-dependent, but did not require GammaDelta T cells, NK T cells, or NK cells. In order to determine whether the anti-tumour T cells are a result of pre-existing immune responses, authors transfer CD44+ memory T cells or CD44- naïve T cells from MM-experienced mice to MM-bearing mice receiving T cell-depleted bone marrow (referred to as BMT+-CD44+ and BMT+-CD44-, respectively), where BMT+-CD44+ mice indicated superior tumour control, confirming that memory T cells are the major player in anti-tumour immunity. After 2 weeks of bone marrow transplantation, BMT+-CD44+ mice harbored more CD8+ T cells, the majority of which were CD44+CD62L- effector memory/effector T cells, compared to BMT+-CD44- mice. Further phenotyping indicated that CD44+CD62L- effector memory/effector T cells in the bone marrow of BMT+-CD44+ mice were a mix of increased levels of activated and exhausted T cells. T cells collected from MM-bearing recipients that had long-term control of disease were antigen-specific, as adoptive transfer of these T cells showed improved control of tumour outcome by expanding central memory T cells that were composed of increased levels of antigen-experienced CD122+ T cells. T cell receptor beta sequencing results showed newly formed T cell colonies in MM-bearing mice treated with bone marrow transplantation, further supporting the occurrence of naïve T cell priming in this setting. IL-17A secreted by donor cells supported MM growth, as adoptive transfer of T cells from IL-17A-/- mice showed better outcome than T cells from wild-type mice. Similar benefits were also observed when IL-17A neutralizing antibodies were administered to recipient mice. Further experiments showed the direct effects of IL-17A in supporting MM progression. IFN-gamma signaling from the donor T cells was essential for anti-tumour effects of bone marrow transplantation, given that T cells from IFN-gamma-/- or IFN-gammaR-/- failed to indicate therapeutic influences. Administration of anti-CD137 agonists improved outcome of MM-bearing mice treated with bone marrow transplantation by increasing T cell numbers in the bone marrow, enhancing CD8+ T cell functions, and reducing the proportion of Treg in CD4+ T cells. More importantly, administration of anti-CD137 agonists followed by PD-1 inhibitors at a late time point reduced tumour burden in MM-bearing mice receiving bone marrow transplantation.
This project highlights the importance of T cells in MM control, suggesting the possible T cell-centred strategies in clinical applications in MM patients.