While application of regulatory T-cells (Tregs) has become a promising tool to prevent Graft-versus-Host Disease (GvHD), Tregs pose the risk of suppressing the curative Graft-versus-Tumor (GvT) effect induced by therapeutically transfused donor lymphocytes. Towards clinical application of Tregs, we explored the in vivo impact of human Tregs on GvT and GvHD in a humanized GvT model. In this model we have previously shown that infusion of human PBMC into tumor bearing Rag2-/-gc-/- mice induces a profound GvT effect but also results in lethal xenogeneic(x) GvHD. We observed that co-infusion of human CD4+CD25+ Tregs suppressed x-GvHD, but allowed effective GvT against human tumors localized within the bone marrow, despite efficient Treg-homing to bone marrow. Remarkably, however, Tregs abrogated the GvT effect against the same tumor when located extramedullary, suggesting that permittance of the GvT effect in the bone marrow was due to the inactivation of Tregs in the bone marrow micro-environment. In detailed exploration of this remarkable phenomenon, we discovered that stromal cells derived from bone marrow neutralize the suppressive phenotype and promotes interleukin-17 in human Tregs through secretion of IL-6/IL-1β. In conclusion, this study for the first time provides a novel in vivo mechanism of how human Tregs can control undesired inflammation while permitting GvT against hematological tumors residing in bone marrow. This mechanism involves the bone marrow stroma, which creates a tumor micro-environment that significantly drives conversion of Tregs into non-suppressor T-cells.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.