Bone Marrow Neutralizes Human Regulatory T-Cells to Permit Graft-Versus-Tumor Immunity In Humanized Mice

Abstract 1017

While application of regulatory T-cells (T_regs) has become a promising tool to prevent Graft-versus-Host Disease (GvHD), T_regs pose the risk of suppressing the curative Graft-versus-Tumor (GvT) effect induced by therapeutically transfused donor lymphocytes. Towards clinical application of T_regs, we explored the in vivo impact of human T_regs 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⁺ T_regs suppressed x-GvHD, but allowed effective GvT against human tumors localized within the bone marrow, despite efficient T_reg-homing to bone marrow. Remarkably, however, T_regs 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 T_regs 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 T_regs through secretion of IL-6/IL-1β. In conclusion, this study for the first time provides a novel in vivo mechanism of how human T_regs 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 T_regs into non-suppressor T-cells.