TGF-β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma

Transforming growth factor beta (TGF-beta) has an important role in mediating T-cell suppression in B-cell non-Hodgkin lymphoma (NHL). However, the underlying mechanism responsible for TGF-beta-mediated inhibition of effector memory T (T-m) cells is largely unknown. As reported here, we show that exhaustion is a major mechanism by which TGF-beta inhibits T-m cells, and TGF-beta mediated exhaustion is associated with upregulation of CD70. We found that TGF-beta upregulates CD70 expression on effector T-m cells while it preferentially induces Foxp3 expression in naive T cells. CD70 induction by TGF-beta is Smad3-dependent and involves IL-2/Stat5 signaling. CD70(+) T cells account for TGF-beta-induced exhaustion of effector T-m cells. Both TGF-beta-induced and preexisting intratumoral CD70(+) effector T-m cells from B-cell NHL have an exhausted phenotype and express higher levels of PD-1 and TIM-3 compared with CD70(-) T cells. Signaling transduction, proliferation and cytokine production are profoundly decreased in these cells, and they are highly susceptible to apoptosis. Clinically, intratumoral CD70-expressing T cells are prevalent in follicular B-cell lymphoma (FL) biopsy specimens, and increased numbers of intratumoral CD70(+) T cells correlate with an inferior patient outcome. These findings confirm TGF-beta-mediated effector T-m cell exhaustion as an important mechanism of immune suppression in B-cell NHL.