Investigation of the effects of LSD1 inhibition on AML immunogenicity and T cell-mediated immune responses

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a curative treatment option for AML. Alloreactive donor T cells can produce the graft-versus-leukemia (GVL) effect which represents a major therapeutic benefit of allo-HSCT. However, evading from allogeneic immune surveillance, potentially through the downregulation of human leukocyte antigen class II (HLA-II) antigen presentation machinery, can contribute to AML relapse. Lysine-specific demethylase 1 (LSD1) is an emerging epigenetic therapeutic target in AML. The present study aims to explore whether LSD1 inhibition can enhance AML immunogenicity to promote T-cell mediated immune response. The immunological effects of a clinical-stage LSD1 inhibitor bomedemstat (IMG-7289) were examined in both human and murine AML cell models in vitro. The results demonstrated that bomedemstat treatment significantly enhanced the expression of class II transactivator (CIITA). It subsequently led to the upregulation of HLA-DR in certain human AML cell lines when stimulated by IFN-γ. Bomedemstat also markedly upregulated the expression of CD86 in all human AML cell lines tested. The study also demonstrated that bomedemstat treatment significantly increased the production of pro-inflammatory cytokines IL-12 and CXCL-10. In murine AML models, bomedemstat concurrently upregulated the expression of major histocompatibility complex class II (MHC-II) and CD86 in H9M-transformed cells without IFN-γ stimulation. This effect was not observed in MN1-transformed cells. Bomedemstat-treated H9M cells were subsequently shown to induce antigen-dependent T cell activation. Functional assays revealed that bomedemstat treatment sensitized H9M cells to antigen-dependent immune killing effect mediated by CD4+ T cells. In conclusion, the current study demonstrates both phenotypically and functionally that LSD1 inhibition by bomedemstat treatment can enhance AML immunogenicity. This is evident by the increased antigen presentation, co-stimulation and production of inflammatory cytokines. These findings suggest that LSD1 inhibition may be a relevant strategy to pursue as a maintenance therapy after allo-HSCT.