Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation

Cristina Toffalori, Laura Zito, Valentina Gambacorta, Michela Riba, Giacomo Oliveira, Gabriele Bucci, Matteo Barcella, Orietta Spinelli, Raffaella Greco, Lara Crucitti, Nicoletta Cieri, Maddalena Noviello, Francesco Manfredi, Elisa Montaldo, Renato Ostuni, Matteo M. Naldini, Bernhard Gentner, Miguel Waterhouse, Robert Zeiser, Jurgen FinkeMaher Hanoun, Dietrich W. Beelen, Ivana Gojo, Leo Luznik, Masahiro Onozawa, Takanori Teshima, Raynier Devillier, Didier Blaise, Constantijn J.M. Halkes, Marieke Griffioen, Matteo G. Carrabba, Massimo Bernardi, Jacopo Peccatori, Cristina Barlassina, Elia Stupka, Dejan Lazarevic, Giovanni Tonon, Alessandro Rambaldi, Davide Cittaro, Chiara Bonini, Katharina Fleischhauer, Fabio Ciceri, Luca Vago

Research output: Contribution to journalLetterpeer-review


Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-γ or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.

Original languageEnglish
Pages (from-to)603-611
Number of pages9
JournalNature Medicine
Issue number4
Publication statusPublished - Apr 1 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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