TY - JOUR
T1 - Flotetuzumab and other T-cell immunotherapies upregulate MHC class II expression on acute myeloid leukemia cells
AU - Rimando, Joseph C.
AU - Chendamarai, Ezhilarasi
AU - Rettig, Michael P.
AU - Jayasinghe, Reyka
AU - Christopher, Matthew J.
AU - Ritchey, Julie K.
AU - Christ, Stephanie
AU - Kim, Miriam Y.
AU - Bonvini, Ezio
AU - DiPersio, John F.
N1 - Funding Information:
This work was supported by grants from the NIH / NCI : K08 Program grant ( CA222630-01 , to M.J.C.), NCI Research Specialist Award ( R50 CA211466 , to M.P.R.), a Genomics of Acute Myeloid Leukemia Program Project grant ( P01 CA101937 , to J.F.D.), and an NCI Outstanding Investigator Award ( R35 CA197561 , to J.F.D.).
Funding Information:
The authors thank the Siteman Flow Cytometry Core for assistance with flow cytometry and the Division of Comparative Medicine at Washington University for their excellent animal care. This work was supported by grants from the National Institutes of Health, National Cancer Institute (NCI): K08 Program grant (CA222630-01, to M.J.C.), NCI Research Specialist Award (R50 CA211466, to M.P.R.), a Genomics of Acute Myeloid Leukemia Program Project grant (P01 CA101937, to J.F.D.), and an NCI Outstanding Investigator Award (R35 CA197561, to J.F.D.). Contribution: J.C.R. E.C. and M.P.R. designed and performed experiments, analyzed data, and wrote the manuscript; R.J. analyzed the single cell RNA-seq data and wrote the manuscript; M.J.C. J.K.R. S.C. and M.Y.K. designed and performed experiments; E.B. contributed flotetuzumab; and J.F.D supervised the project, designed the research, and reviewed and edited the manuscript.
Publisher Copyright:
© 2023 The American Society of Hematology
PY - 2023/4/6
Y1 - 2023/4/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85147863374&partnerID=8YFLogxK
U2 - 10.1182/blood.2022017795
DO - 10.1182/blood.2022017795
M3 - Article
C2 - 36563336
AN - SCOPUS:85147863374
SN - 0006-4971
VL - 141
SP - 1718
EP - 1723
JO - Blood
JF - Blood
IS - 14
ER -