Targeting MDM2 enhances antileukemia immunity after allogeneic transplantation via MHC-II and TRAIL-R1/2 upregulation

Jenny N.H.G. Ho, Dominik Schmidt, Theresa Lowinus, Jeongmin Ryoo, Elaine Pashupati Dopfer, Nicolás Gonzalo Núñez, Sara Costa-Pereira, Cristina Toffalori, Marco Punta, Viktor Fetsch, Tobias Wertheimer, Marie Claire Rittmann, Lukas M. Braun, Marie Follo, Christelle Briere, Janaki Manoja Vinnakota, Marlene Langenbach, Felicitas Koppers, Khalid Shoumariyeh, Helena EngelTamina Rückert, Melanie Märklin, Samuel Holzmayer, Anna L. Illert, Federica Magon, Geoffroy Andrieux, Sandra Duquesne, Dietmar Pfeifer, Julian Staniek, Marta Rizzi, Cornelius Miething, Natalie Köhler, Justus Duyster, Hans D. Menssen, Melanie Boerries, Joerg M. Buescher, Nina Cabezas-Wallscheid, Bruce R. Blazar, Petya Apostolova, Luca Vago, Erika L. Pearce, Burkhard Becher, Robert Zeiser

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Patients with acute myeloid leukemia (AML) often achieve remission after allogeneic hematopoietic cell transplantation (allo-HCT) but subsequently die of relapse driven by leukemia cells resistant to elimination by allogeneic T cells based on decreased major histocompatibility complex II (MHC-II) expression and apoptosis resistance. Here we demonstrate that mouse-double-minute-2 (MDM2) inhibition can counteract immune evasion of AML. MDM2 inhibition induced MHC class I and II expression in murine and human AML cells. Using xenografts of human AML and syngeneic mouse models of leukemia, we show that MDM2 inhibition enhanced cytotoxicity against leukemia cells and improved survival. MDM2 inhibition also led to increases in tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2 (TRAIL-R1/2) on leukemia cells and higher frequencies of CD8+CD27lowPD-1lowTIM-3low T cells, with features of cytotoxicity (perforin+CD107a+TRAIL+) and longevity (bcl-2+IL-7R+). CD8+ T cells isolated from leukemia-bearing MDM2 inhibitor-treated allo-HCT recipients exhibited higher glycolytic activity and enrichment for nucleotides and their precursors compared with vehicle control subjects. T cells isolated from MDM2 inhibitor-treated AML-bearing mice eradicated leukemia in secondary AML-bearing recipients. Mechanistically, the MDM2 inhibitor-mediated effects were p53-dependent because p53 knockdown abolished TRAIL-R1/2 and MHC-II upregulation, whereas p53 binding to TRAILR1/2 promotors increased upon MDM2 inhibition. The observations in the mouse models were complemented by data from human individuals. Patient-derived AML cells exhibited increased TRAIL-R1/2 and MHC-II expression on MDM2 inhibition. In summary, we identified a targetable vulnerability of AML cells to allogeneic T-cell–mediated cytotoxicity through the restoration of p53-dependent TRAIL-R1/2 and MHC-II production via MDM2 inhibition.

Original languageEnglish (US)
Pages (from-to)1167-1181
Number of pages15
JournalBlood
Volume140
Issue number10
DOIs
StatePublished - Sep 8 2022

Bibliographical note

Funding Information:
This study is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), SFB-1479 – Project ID: 441891347, SFB TRR167 (to R.Z., M.B., and M.P.), SFB-1453 – Project-ID 431984000 (to M.B.), and SFB1160 (to M.B., M.R., and R.Z.); ERC Consolidator grant (681012 GvHDCure to R.Z.); Germany's Excellence Strategy (CIBSS – EXC-2189 – Project ID 390939984 to R.Z. and N.K.); and INTERREG V European regional development fund (European Union) program (project 3.2 TRIDIAG to R.Z.). P.A. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - project number 492259164, and by the Deutsches Konsortium für Translationale Krebsforschung (DKTK, German Cancer Consortium) – project number FR01-375. J.R. is supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2019R1A6A3A03032009). M.B. is supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (coNfirm, FKZ 01ZX1708F) and within the Medical Informatics Funding Scheme (MIRACUM, FKZ 01ZZ1606A-H). B.R.B. received funding from the National Institutes of Health R01 HL56067 and R37 AI34495. B.B. received funding through the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program grant agreement No. 882424 (ERC-AdG:IMPACT), the Swiss National Science foundation CRSII5_183478 and 310030_188450, and the University Priority Project translational cancer research.

Funding Information:
The authors thank the Lighthouse Core Facility for cell sorting; Heide Dierbach and Katja Graewe for tissue processing and staining; and the Metabolomics Core Facility at the Max Planck Institute of Immunobiology and Epigenetics, Freiburg, for chromatography-mass spectrometry measurements. This study is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), SFB-1479 – Project ID: 441891347, SFB TRR167 (to R.Z. M.B. and M.P.), SFB-1453 – Project-ID 431984000 (to M.B.), and SFB1160 (to M.B. M.R. and R.Z.); ERC Consolidator grant (681012 GvHDCure to R.Z.); Germany's Excellence Strategy (CIBSS – EXC-2189 – Project ID 390939984 to R.Z. and N.K.); and INTERREG V European regional development fund (European Union) program (project 3.2 TRIDIAG to R.Z.). P.A. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - project number 492259164, and by the Deutsches Konsortium für Translationale Krebsforschung (DKTK, German Cancer Consortium) – project number FR01-375. J.R. is supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2019R1A6A3A03032009). M.B. is supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (coNfirm, FKZ 01ZX1708F) and within the Medical Informatics Funding Scheme (MIRACUM, FKZ 01ZZ1606A-H). B.R.B. received funding from the National Institutes of Health R01 HL56067 and R37 AI34495. B.B. received funding through the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program grant agreement No. 882424 (ERC-AdG:IMPACT), the Swiss National Science foundation CRSII5_183478 and 310030_188450, and the University Priority Project translational cancer research.

Publisher Copyright:
© 2022 American Society of Hematology

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