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Calreticulin exposure on malignant blasts correlates with improved natural killer cell-mediated cytotoxicity in acute myeloid leukemia patients
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SYSNO ASEP 0537960 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Calreticulin exposure on malignant blasts correlates with improved natural killer cell-mediated cytotoxicity in acute myeloid leukemia patients Author(s) Truxová, I. (CZ)
Kašíková, L. (CZ)
Šálek, C. (CZ)
Hensler, M. (CZ)
Lysák, D. (CZ)
Holicek, P. (CZ)
Bílková, P. (CZ)
Holubová, M. (CZ)
Chen, X. (US)
Mikyšková, Romana (UMG-J) RID
Reiniš, Milan (UMG-J) RID
Kovář, Marek (MBU-M) RID, ORCID
Tomalová, Barbora (MBU-M) ORCID
Kline, J.P. (US)
Galluzzi, L. (US)
Špíšek, R. (CZ)
Fučíková, J. (CZ)Number of authors 17 Source Title Haematologica-The Hematology Journal. - : Fondazione Ferrata Storti - ISSN 0390-6078
Roč. 105, č. 7 (2020), s. 1868-1878Number of pages 11 s. Publication form Online - E Language eng - English Country IT - Italy Keywords nk cells ; dendritic cells ; tumor-cells ; immunity ; death ; expression ; growth ; cancer ; il-15 Subject RIV EB - Genetics ; Molecular Biology OECD category Immunology Subject RIV - cooperation Institute of Microbiology - Microbiology, Virology Method of publishing Open access Institutional support UMG-J - RVO:68378050 ; MBU-M - RVO:61388971 UT WOS 000550445700017 DOI 10.3324/haematol.2019.223933 Annotation 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 responses in vivo, thus having a major impact on patient prognosis. We have previously demonstrated that the presence of calreticulin on the surface of malignant 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(+)CD14(high) cells that, upon exposure to CRT, express higher levels of IL-15R alpha, 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(+)CD14(high) cells have increased capacity to migrate to secondary lymphoid organs, where can efficiently deliver stimulatory signals (IL-15R alpha/IL15) to NK cells. These findings delineate a multipronged, clinically relevant mechanism whereby surface-exposed calreticulin favors NK-cell activation in AML patients. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2021 Electronic address https://haematologica.org/article/view/9938
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