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

INSERM U1138 Centre de Recherche des Cordeliers Paris France Université Pierre et Marie Curie Paris 6 Paris France Université Paris Descartes Paris 5 Paris France

INSERM U1138 Centre de Recherche des Cordeliers Paris France Université Pierre et Marie Curie Paris 6 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

INSERM U1138 Centre de Recherche des Cordeliers Paris France Université Pierre et Marie Curie Paris 6 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

INSERM U1138 Centre de Recherche des Cordeliers Paris France Université Pierre et Marie Curie Paris 6 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

Institute of Clinical and Experimental Hematology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Hematology and Blood Transfusion Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Sotio Prague Czech Republic

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