TY - JOUR
T1 - Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation
AU - Toffalori, Cristina
AU - Zito, Laura
AU - Gambacorta, Valentina
AU - Riba, Michela
AU - Oliveira, Giacomo
AU - Bucci, Gabriele
AU - Barcella, Matteo
AU - Spinelli, Orietta
AU - Greco, Raffaella
AU - Crucitti, Lara
AU - Cieri, Nicoletta
AU - Noviello, Maddalena
AU - Manfredi, Francesco
AU - Montaldo, Elisa
AU - Ostuni, Renato
AU - Naldini, Matteo M.
AU - Gentner, Bernhard
AU - Waterhouse, Miguel
AU - Zeiser, Robert
AU - Finke, Jurgen
AU - Hanoun, Maher
AU - Beelen, Dietrich W.
AU - Gojo, Ivana
AU - Luznik, Leo
AU - Onozawa, Masahiro
AU - Teshima, Takanori
AU - Devillier, Raynier
AU - Blaise, Didier
AU - Halkes, Constantijn J.M.
AU - Griffioen, Marieke
AU - Carrabba, Matteo G.
AU - Bernardi, Massimo
AU - Peccatori, Jacopo
AU - Barlassina, Cristina
AU - Stupka, Elia
AU - Lazarevic, Dejan
AU - Tonon, Giovanni
AU - Rambaldi, Alessandro
AU - Cittaro, Davide
AU - Bonini, Chiara
AU - Fleischhauer, Katharina
AU - Ciceri, Fabio
AU - Vago, Luca
N1 - Funding Information:
This work was supported by the Italian Ministry of Health (no. RF-FSR-2008-1202648 to K.F., F.C. and C.Barlassina, no. RF-2011-02351998 to F.C. and L.V., no. RF-2011-02348034 to L.V. and TRANSCAN HLALOSS to L.V. and K.F.), by the Italian Ministry of University and Research (no. MIUR-2015NZWSEC-001 to C.Bonini), by the CARIPLO Foundation (no. 2009-2665 to K.F., A.R. and C.Barlassina), by the Associazione Italiana per la Ricerca sul Cancro (IG no. 18458 to C.Bonini, IG no. 12042 to K.F. and F.C. and Start-Up Grant no. 14162 to L.V.), by the ASCO Conquer Cancer Foundation (2014 Young Investigator Award to L.V.), EU-FP7 (SUPERSIST to C.Bonini), the Deutsche José Carreras Leukämie Stiftung (grant nos. DJCLS R 15-02 and DJCLS 01R/2017 to K.F.) and by the DKMS Mechtild Harf Foundation (DKMS Mechtild Harf Research Grant 2015 to L.V.). C.T. was supported by an Associazione Italiana per la Ricerca sul Cancro postdoctoral fellowship. G.O. was supported by a Fondazione Matarelli fellowship from the Associazione Italiana Leucemie and by a Fondazione Umberto Veronesi fellowship.
Funding Information:
C.Bonini received research support from Molmed s.p.a and Intellia Therapeutics. K.F. received research support from GenDx. L.V. received research support from GenDx and Moderna Therapeutics. None of the other authors has any relevant conflicts of interest to disclose.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41591-019-0400-z
DO - 10.1038/s41591-019-0400-z
M3 - Article
C2 - 30911134
AN - SCOPUS:85063422613
SN - 1078-8956
VL - 25
SP - 603
EP - 611
JO - Nature medicine
JF - Nature medicine
IS - 4
ER -