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.

Caryl and Israel Englander Institute for Precision Medicine New York NY USA

Committee on Immunology University of Chicago Chicago IL USA

Department of Dermatology Yale School of Medicine New Haven CT USA

Department of Hematology and Oncology University Hospital in Pilsen Czech Republic

Department of Immunology Charles University 2 Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Medicine University of Chicago Chicago IL USA

Department of Radiation Oncology Weill Cornell Medical College New York NY USA

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

Institute of Hematology and Blood Transfusion Prague Czech Republic

Laboratory of Immunological and Tumour models Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Tumor Biology and Immunotherapy Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Laboratory of Tumor Immunology Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

Sandra and Edward Meyer Cancer Center New York NY USA

Sotio Prague Czech Republic

Universite de Paris Paris France

University of Chicago Comprehensive Cancer Center Chicago IL USA

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