Flotetuzumab and other T-cell immunotherapies upregulate MHC class II expression on acute myeloid leukemia cells

•T-cell immunotherapies targeting AML antigens upregulate MHC-II expression on AML cells.•IFN-γ mediates the T-cell immunotherapy-induced MHC-II upregulation on AML cells. [Display omitted] Acute myeloid leukemia (AML) relapse is one of the most common and significant adverse events following allogeneic hematopoietic cell transplantation (HCT). Downregulation of major histocompatibility class II (MHC-II) surface expression on AML blasts may represent a mechanism of escape from the graft-versus-malignancy effect and facilitate relapse. We hypothesized that T-cell immunotherapies targeting AML antigens would upregulate MHC-II surface expression via localized release of interferon gamma (IFN-γ), a protein known to upregulate MHC-II expression via JAK-STAT signaling. We demonstrate that flotetuzumab (FLZ), a CD123 × CD3 bispecific DART molecule, and chimeric antigen receptor expressing T cells targeting CD123, CD33, or CD371 upregulate MHC-II surface expression in vitro on a THP-1 AML cell line with intermediate MHC-II expression and 4 primary AML samples from patients relapsing after HCT with low MHC-II expression. We additionally show that FLZ upregulates MHC-II expression in a patient-derived xenograft model and in patients with relapsed or refractory AML who were treated with FLZ in a clinical trial. Finally, we report that FLZ-induced MHC-II upregulation is mediated by IFN-γ. In conclusion, we provide evidence that T-cell immunotherapies targeting relapsed AML can kill AML via both MHC-independent mechanisms and by an MHC-dependent mechanism through local release of IFN-γ and subsequent upregulation of MHC-II expression. Rimando et al explore T-cell–engaging immunotherapeutic approaches to salvage relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT). Using cell lines and primary AML cells in vitro and in xenogeneic transplant models, the authors defined how both the dual-affinity retargeting compound flotetuzumab and chimeric antigen receptor T cells against AML-associated surface antigens induced upregulation of major histocompatibility (MHC) class II molecules via interferon-gamma signaling. These data advance prospects for improved post-HCT therapy for currently incurable AML.