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Calreticulin exposure on malignant blasts correlates with improved natural killer cell-mediated cytotoxicity in acute myeloid leukemia patients
- Source :
- Haematologica
- Publication Year :
- 2019
- Publisher :
- Ferrata Storti Foundation (Haematologica), 2019.
-
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 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+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 lymphoid 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.
- Subjects :
- Cytotoxicity, Immunologic
Acute Myeloid Leukemia
CD11c
Lymphocyte Activation
Mice
Immune system
Interferon
Animals
Humans
Medicine
Cytotoxic T cell
Interleukin-15
CD86
biology
business.industry
Myeloid leukemia
Articles
Hematology
Killer Cells, Natural
Leukemia, Myeloid, Acute
Cancer cell
Cancer research
biology.protein
Calreticulin
business
medicine.drug
Subjects
Details
- ISSN :
- 15928721 and 03906078
- Volume :
- 105
- Database :
- OpenAIRE
- Journal :
- Haematologica
- Accession number :
- edsair.doi.dedup.....c58736eab9afb71f8944921bca96ddbb