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Ferrata Storti Foundation
Haematologica 2020 Volume 105(7):1868-1878
Acute Myeloid Leukemia
Calreticulin exposure on malignant blasts correlates with improved natural killer cell-mediated cytotoxicity in acute myeloid leukemia patients
Iva Truxova,1 Lenka Kasikova,1,2 Cyril Salek,3,4 Michal Hensler,1 Daniel Lysak,5 Peter Holicek,1,2 Pavla Bilkova,1 Monika Holubova,6 Xiufen Chen,7 Romana Mikyskova,8 Milan Reinis,8 Marek Kovar,9 Barbora Tomalova,9 Justin P. Kline,7,10,11 Lorenzo Galluzzi,12,13,14,15,16 Radek Spisek1,2 and Jitka Fucikova1,2
1 2 nd
Sotio, Prague, Czech Republic; Department of Immunology, Charles University, 2 Faculty
of Medicine and University Hospital Motol, Prague, Czech Republic; 3Institute of Hematology and Blood Transfusion, Prague, Czech Republic; 4Institute of Clinical and Experimental Hematology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic; 5Department of Hematology and Oncology, University Hospital in Pilsen, Czech Republic; 6Laboratory of Tumor Biology and Immunotherapy, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic; 7Department of Medicine, University of Chicago, Chicago, IL, USA; 8Laboratory of Immunological and Tumour models, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic; 9Laboratory of Tumor Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic; 10Committee on Immunology, University of Chicago, Chicago, IL, USA; 11University of Chicago Comprehensive Cancer Center, Chicago, IL, USA; 12Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; 13Sandra and Edward Meyer Cancer Center, New York, NY, USA; 14Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA; 15Department of Dermatology, Yale School of Medicine, New Haven, CT, USA and 16Universite de Paris, Paris, France
ABSTRACT
In some settings, cancer cells responding to treatment undergo an immunogenic form of cell death that is associated with the abundant emission of danger signals in the form of damage-associated molecular patterns. Accumulating preclinical and clinical evidence indicates that danger signals play a crucial role in the (re-)activation of antitumor immune respons- es in vivo, thus having a major impact on patient prognosis. We have previ- ously demonstrated that the presence of calreticulin on the surface of malig- nant blasts is a positive prognostic biomarker for patients with acute myeloid leukemia (AML). Calreticulin exposure not only correlated with enhanced T-cell-dependent antitumor immunity in this setting but also affected the number of circulating natural killer (NK) cells upon restoration of normal hematopoiesis. Here, we report that calreticulin exposure on malignant blasts is associated with enhanced NK cell cytotoxic and secretory functions, both in AML patients and in vivo in mice. The ability of calreticulin to stimulate NK-cells relies on CD11c+CD14high cells that, upon exposure to CRT, express higher levels of IL-15Rα, maturation markers (CD86 and HLA- DR) and CCR7. CRT exposure on malignant blasts also correlates with the upregulation of genes coding for type I interferon. This suggests that CD11c+CD14high cells have increased capacity to migrate to secondary lym- phoid organs, where can efficiently deliver stimulatory signals (IL-15Rα/IL- 15) to NK cells. These findings delineate a multipronged, clinically relevant mechanism whereby surface-exposed calreticulin favors NK-cell activation in AML patients.
Introduction
In response to some treatments including anthracycline-based chemotherapy, high hydrostatic pressure or radiation therapy, cancer cells mount unsuccessful adaptive responses to stress that are accompanied by the release of endogenous
Correspondence:
JITKA FUCIKOVA
fucikova@sotio.com
Received: April 8, 2019. Accepted: September 26, 2019. Pre-published: October 3, 2019.
doi:10.3324/haematol.2019.223933
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/7/1868
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