As one of the most validated immunotherapies to date, allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative option for high-risk hematological malignancies, particularly acute myeloid leukemia (AML). The immunotherapeutic activity of allo-HCT is known as the graft-vs-leukemia (GVL) activity. However, GVL activity is often accompanied by T-cell reactivity to allo-antigens in normal host tissues, which leads to graft-versus-host disease (GVHD), another major cause of death after HCT. Therefore, there is a great unmet need to improve the current process of allo-HCT through increasing the GVL activity and decreasing GVHD. We have shown that an elevated plasma level of soluble (s)ST2 in HCT patients is a risk factor for severe GVHD. ST2 blockade reduces sST2-producing T cells while maintaining protective membrane (m)ST2-expressing T cells such as type 2 T cells and regulatory T cells during aGVHD. A novel IL-9 producing T helper subset, Th9, expresses mST2. Furthermore, Th9 cells and IL-9 producing CD8 cytotoxic (Tc9) cells have higher antitumor activity than Th1 and Tc1 cells in melanoma models. Interestingly, we found that the addition of IL-33 during T9 differentiation (T9IL-33) increased expression of mST2 and PU.1, a transcription factor that promotes IL-9 production in both CD4 and CD8 T cells. Adoptive transfer of T9IL-33 cells with bone marrow cells in a murine model of HCT resulted in less severe GVHD compared to transfer of T9IL-33 cells generated from ST2−/− or IL-9−/− T cells. Furthermore, cytolytic molecules implicated in anti-leukemic activity (granzyme B and perforin) were upregulated in WT T9IL-33 cells while ST2−/− T9IL-33 cells did not. WT T9IL-33 cells also exhibited higher anti-leukemic activity when cultured with a retrovirally transduced MLL-AF9 leukemic cells in comparison to ST2−/− T9IL-33 in in vitro cytolytic assays. In vivo GVL experiments with MLL-AF9 AML and adoptive transfer of T9IL-33 cells resulted in increased survival compared to syngeneic mice, allo-HCT mice transferred with T1 cells, or T9 cells or T9IL-33 cells generated from ST2−/− or IL-9−/− T cells. Human T9 cells are poorly studied. Here we demonstrate that IL-33 has the same impact on human T cells through enhancing IL-9 and Granzyme B production compared to T9 cells as well as demonstrated higher in vitro anti-leukemic cytolytic activity when incubated with MOLM14, an aggressive AML tumor cell line expressing FLT3/ITD mutations. Importantly, CD8α expression was upregulated in WT T9IL-33 (both CD4 and CD8) cells in comparison to ST2−/− T9IL-33 cells, and CD8α blockade with neutralizing antibody during allogeneic specific T9IL-33 differentiation reduced cytotoxicity of both murine T9IL-33, and human T9IL-33 cells as compared to the cell blocked with isotype control, suggesting that CD8α was associated with MHC-restricted cytolytic activity in T9IL-33 cells. Altogether, our observations demonstrated that adoptive transfer of T9IL-33 cells represents a promising cellular therapy following HCT.
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