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

Author:

Ho Jenny N. H. G.1,Schmidt Dominik12,Lowinus Theresa1,Ryoo Jeongmin12ORCID,Dopfer Elaine-Pashupati1,Gonzalo Núñez Nicolás3,Costa-Pereira Sara3ORCID,Toffalori Cristina4,Punta Marco45ORCID,Fetsch Viktor1,Wertheimer Tobias3ORCID,Rittmann Marie-Claire1ORCID,Braun Lukas M.12ORCID,Follo Marie1,Briere Christelle1,Vinnakota Janaki Manoja12,Langenbach Marlene12,Koppers Felicitas1,Shoumariyeh Khalid16,Engel Helena1ORCID,Rückert Tamina1,Märklin Melanie78ORCID,Holzmayer Samuel78,Illert Anna L.16,Magon Federica1,Andrieux Geoffroy69ORCID,Duquesne Sandra1,Pfeifer Dietmar1,Staniek Julian210,Rizzi Marta1011,Miething Cornelius16ORCID,Köhler Natalie112ORCID,Duyster Justus16ORCID,Menssen Hans D.13,Boerries Melanie69ORCID,Buescher Joerg M.14ORCID,Cabezas-Wallscheid Nina14,Blazar Bruce R.15ORCID,Apostolova Petya1416,Vago Luca4ORCID,Pearce Erika L.1416,Becher Burkhard3ORCID,Zeiser Robert1611ORCID

Affiliation:

1. 1Clinic of Internal Medicine I, Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine, Medical Centre, University of Freiburg, Freiburg, Germany;

2. 2Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany;

3. 3Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland;

4. 4Unit of Immunogenetics, Leukemia Genomics and Immunobiology, Division of Immunology, Transplantation and Infectious Disease, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milano, Italy;

5. 5Center for Omics Sciences, IRCCS San Raffaele Institute, Milano, Italy;

6. 6German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research, Center (DKFZ), Heidelberg, Germany;

7. 7Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tuebingen, Tuebingen, Germany;

8. 8Deutsche Forschungsgemeinschaft Cluster of Excellence 2180 “Image-guided and Functional Instructed Tumor Therapy,” University of Tuebingen, Tuebingen, Germany;

9. 9Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany,

10. 10Department of Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Centre,

11. 11Signalling Research Centres BIOSS and CIBSS – Centre for Integrative Biological, Signalling Studies, and

12. 12CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany;

13. 13Novartis Pharma, Basel, Switzerland;

14. 14Max-Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany;

15. 15Division of Blood & Marrow Transplant and Cellular Therapy, Department of Pediatrics, University of Minnesota, Minneapolis, MN; and

16. 16The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Johns Hopkins University, Baltimore, MD

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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