Calreticulin exposure on malignant blasts correlates with improved natural killer cell-mediated cytotoxicity in acute myeloid leukemia patients
Abstrakt
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. Calreticulin exposure not only correlated with enhanced T cell-dependent antitumor immunity in this setting but also affected the number of circulating natural killer cells upon restoration of normal hematopoiesis.
Here, we report that calreticulin exposure on malignant blasts is associated with enhanced natural killer cell cytotoxic and secretory functions, both in acute myeloid leukemia patients and in vivo in mice. The ability of calreticulin to stimulate natural killer 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 natural killer cells.
These findings delineate a multipronged, clinically relevant mechanism whereby surface-exposed calreticulin favors natural killer cell activation in acute myeloid leukemia patients.