Tumour Cell Generation of Inducible Regulatory T-Cells in Multiple Myeloma Is Contact-Dependent and Antigen-Presenting Cell-Independent

Abstract

Regulatory T-cells (TReg cells) are increased in patients with multiple myeloma (MM). We investigated whether MM cells could generate and/or expand TReg cells as a method of immuno-surveillance avoidance. In an in vitro model, CD4+CD25- FoxP3 - T-cells co-cultured with malignant plasma cells (primary MM cells and cell lines) induced a significant generation of CD4+CD25+ FoxP3 + inducible TReg cells (tTReg cells; p<0.0001), in a contact-dependent manner. tTReg cells were polyclonal, demonstrated a suppressive phenotype and phenotypically, demonstrated increased FoxP3 (p = 0.0001), increased GITR (p<0.0001), increased PD1 (p = 0.003) and decreased CD62L (p = 0.007) expression compared with naturally occurring TReg cells. FACS-sorted tTReg cells differentiated into FoxP +IL-17+ and FoxP3 -IL-17+ CD4+ cells upon TCR-mediated stimulation. Blocking experiments with anti-ICOS-L MoAb resulted in a significant inhibition of tTReg cell generation whereas both IL-10 & TGFβ blockade did not. MM tumour cells can directly generate functional TReg cells in a contact-dependent manner, mediated by ICOS/ICOS-L. These features suggest that tumour generation of TReg cells may contribute to evasion of immune surveillance by the host.

CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs

“…This finding could reflect an advantageous (in terms of proliferation) environment established by the malignant cells. 7 Similar to multiple myeloma, 35 cell-to-cell contact was not a strict prerequisite for T Reg induction, but rather acted as a significant boost. In this context, we could show that monocytes were a significant enforcer of CLL-cell-mediated T Reg induction further corroborating the notion of an active crosstalk between CLL cells and the suppressive immune cell subsets.…”

“…by guest www.bloodjournal.org From confirmed their activity in suppressing autologous T-cell responses ( Figure 4C). The T Regs displayed a preferential cell division 35 when compared with conventional T cells after coculture with malignant cells ( Figure 4D). This observation was strongly supported by our findings in CLL patients, in whom skewed ratios between proliferating Ki67 1 T Regs and conventional T cells (T conv ) correlated significantly with the number of circulating tumor cells ( Figure 4D).…”

GITR+ regulatory T cells in the treatment of autoimmune diseases

“…Furthermore, dendritic cells from the livers of GITRL −/− mice are less efficient at inducing proliferation of antigen-specific Tregs in vitro than the same cells from wild-type littermates [58]. Interestingly, CD4 + effector T cells cocultured with malignant plasma cells induced the generation of pTregs showing high GITR expression [59]. The generation of pTregs was contact-dependent, did not depend on IL-10 or TGF-β, and involved inducible costimulator (ICOS)/ICOSL signaling.…”

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

“…The myeloma-promoting role of Tregs is reinforced by observations in MM patients showing a shorter survival for patients with high Treg percentages [50] and indicating that the number of Tregs is a predictive marker for the risk of disease progression [60]. The finding that MM cells are able to induce the generation of Tregs in vitro further corroborates these results [61]. Furthermore, Tregs have been shown to expand and accumulate in the bone marrow of MM patients after allogeneic stem cell transplantation, and Tregs found in these patients are endowed with a strong inhibitory function, potentially inhibiting anti-myeloma immune control after transplantation [62].…”