Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients.
Cancer cell death can be perceived as immunogenic by the host only when malignant cells emit immunostimulatory signals (so-called "damage-associated molecular patterns," DAMPs), as they die in the context of failing adaptive responses to stress. Accumulating preclinical and clinical evidence indicates that the capacity of immunogenic cell death to (re-)activate an anticancer immune response is key to the success of various chemo- and radiotherapeutic regimens. Malignant blasts from patients with acute myeloid leukemia (AML) exposed multiple DAMPs, including calreticulin (CRT), heat-shock protein 70 (HSP70), and HSP90 on their plasma membrane irrespective of treatment. In these patients, high levels of surface-exposed CRT correlated with an increased proportion of natural killer cells and effector memory CD4+and CD8+T cells in the periphery. Moreover, CRT exposure on the plasma membrane of malignant blasts positively correlated with the frequency of circulating T cells specific for leukemia-associated antigens, indicating that ecto-CRT favors the initiation of anticancer immunity in patients with AML. Finally, although the levels of ecto-HSP70, ecto-HSP90, and ecto-CRT were all associated with improved relapse-free survival, only CRT exposure significantly correlated with superior overall survival. Thus, CRT exposure represents a novel powerful prognostic biomarker for patients with AML, reflecting the activation of a clinically relevant AML-specific immune response.
Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.|Sotio, Prague, Czech Republic.
Jitka
J
Fucikova
Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.|Sotio, Prague, Czech Republic.
Iva
I
Truxova
Sotio, Prague, Czech Republic.
Michal
M
Hensler
INSERM, U1138, Centre de Recherche des Cordeliers, Paris, France.|Université Pierre et Marie Curie/Paris VI, Paris, France.|Université Paris Descartes/Paris 5, Paris, France.
Etienne
E
Becht
Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.|Sotio, Prague, Czech Republic.
Lenka
L
Kasikova
Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.|Sotio, Prague, Czech Republic.
Irena
I
Moserova
Sotio, Prague, Czech Republic.
Sarka
S
Vosahlikova
Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.
Jana
J
Klouckova
INSERM, U1138, Centre de Recherche des Cordeliers, Paris, France.|Université Pierre et Marie Curie/Paris VI, Paris, France.|Université Paris Descartes/Paris 5, Paris, France.
Sarah E
SE
Church
INSERM, U1138, Centre de Recherche des Cordeliers, Paris, France.|Université Pierre et Marie Curie/Paris VI, Paris, France.|Université Paris Descartes/Paris 5, Paris, France.
Isabelle
I
Cremer
INSERM, U1138, Centre de Recherche des Cordeliers, Paris, France.|Université Pierre et Marie Curie/Paris VI, Paris, France.|Université Paris Descartes/Paris 5, Paris, France.|Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
Oliver
O
Kepp
INSERM, U1138, Centre de Recherche des Cordeliers, Paris, France.|Université Pierre et Marie Curie/Paris VI, Paris, France.|Université Paris Descartes/Paris 5, Paris, France.|Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.|Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.|Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
Guido
G
Kroemer
INSERM, U1138, Centre de Recherche des Cordeliers, Paris, France.|Université Pierre et Marie Curie/Paris VI, Paris, France.|Université Paris Descartes/Paris 5, Paris, France.|Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Gustave Roussy Cancer Campus, Villejuif, France.|Department of Radiation Oncology, Weill Cornell Medical College, New York, NY.
Lorenzo
L
Galluzzi
Institute of Hematology and Blood Transfusion, Prague, Czech Republic; and.|Institute of Clinical and Experimental Hematology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
Cyril
C
Salek
Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.|Sotio, Prague, Czech Republic.
Radek
R
Spisek
D000067531:Alarmins / Q000378:metabolism; D001752:Blast Crisis / Q000276:immunology* / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D037282:Calreticulin / Q000378:metabolism*; D016923:Cell Death; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007109:Immunity; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010641:Phenotype; D016016:Proportional Hazards Models; D018417:Th1 Cells / Q000276:immunology; D014158:Transcription, Genetic; D016896:Treatment Outcome
D000067531:Alarmins; C576483:CALR protein, human; D037282:Calreticulin; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins