IL-33/ST2 activation of IL-9-secreting T cells alters the balance of fatal immunity and tumor immunity (TRAN1P.926)

Abstract

Abstract Allogeneic hematopoietic cell transplantation (HCT) is the most potent curative therapy for cancers of the bone marrow; however, graft-versus-host disease (GVHD) continues to be the major limitation to successful HCT, with mortality rates around 50%. Current strategies to suppress GVHD also compromise the beneficial graft-versus-tumor (GVT) activity. We have shown that elevated IL-33-sequestering soluble ST2 in the plasma is a risk factor for severe GVHD. In addition, the IL-9-secreting Th9 and Tc9 cell subsets have higher antitumor activity than Th1 and Tc1. We hypothesized that induction of the ST2/IL-33 pathway will both alleviate GVHD and increase GVT activity. Differentiation of Th9 with IL-33 increased expression of membrane ST2 (ST2L) and PU.1, a transcription factor that promotes IL-9 production. Adoptive transfer of IL-33-treated Th9 cells with bone marrow cells in HCT murine models showed less severe GVHD compared to Th9 without IL-33, or Th2 cells that are protective of GVHD. Polarization of total T cells with IL-33 to IL-9 secreting cells showed that IL-9 was also increased in Tc9 cells via Th9 help. Transcriptome analysis of IL-33-T9 cells showed increased expression of genes with anti-tumor activity. Higher GVT activity with IL-33-T9 cells was demonstrated in models of GFP+MLL-AF9 acute myeloid leukemia. Human IL-33-T9 cells also showed a strong anti-leukemia cytolytic activity. Thus, IL-33-T9 cells represent a promising curative cellular therapy following HCT.