Human forkhead box P3 (FOXP3)+ T cells can be divided into three main functional groups: highly suppressive FOXP3hiCD25hiCD45RA− TReg cells, 'naive' FOXP3lowCD25lowCD45RA+ TReg cells (which give rise to highly suppressive TReg cells following antigenic stimulation) and FOXP3lowCD25lowCD45RA− T cells, which do not show suppressive activity but which instead express pro-inflammatory cytokines. The authors found that these populations differed in terms of CCR4 expression: naive TReg cells showed little to no expression, non-TReg cells expressed intermediate levels and suppressive TReg cells expressed high levels of CCR4. Furthermore, CCR4+ suppressive TReg cells were abundant in tumour tissues, including in those from patients with melanoma. This suggested that CCR4 could be used to specifically deplete highly suppressive TReg cells from patients with cancer. In theory, this strategy would remove detrimental TReg cell effects, while preserving any antitumour effects of FOXP3+ T cells that produce pro-inflammatory cytokines and minimizing the risk of inducing autoimmunity by maintaining naive TReg cell populations.
But can this work in humans? The author used either CD25-specific or CCR4 -specific antibodies to deplete TReg cells from peripheral blood mononuclear cells (PBMCs) of healthy donors or patients with melanoma. Both protocols amplified in vitro effector-type CD4+ T cell responses to NY-ESO-1, which is a tumour-associated antigen. Similarly, in PBMCs isolated from patients with melanoma, CD8+ T cell responses against NY-ESO-1 were boosted when CCR4-specific antibodies were used to deplete TReg cells. Finally, the authors administered a CCR4-specific monoclonal antibody to patients with ATL. Notably, the ATL cells in these patients resemble naturally occurring TReg cells and also express CCR4. The authors found that the CCR4-specific monoclonal antibody effectively depleted both ATL cells and FOXP3hiCD45RA− T cells from patients with ATL, and furthermore, induced the development of effector NY-ESO-1-specific CD8+ T cells in one patient whose ATL cells expressed this tumour-associated antigen.
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