High-throughput drug screening identifies SMAC mimetics as enhancers of NK-cell cytotoxicity in chronic myeloid leukemia
Abstract
Abstract Natural killer (NK) cells have proven to be safe and effective immunotherapies, associated with favorable treatment responses in chronic myeloid leukemia (CML). Augmenting NK-cell function with oncological drugs could improve NK-cell–based immunotherapies. Here, we used a high-throughput drug screen consisting of >500 small-molecule compounds, to systematically evaluate the effects of oncological drugs on primary NK cells against CML cells. We identified second mitochondrially derived activator of caspases (SMAC) mimetics as potent enhancers of NK-cell cytotoxicity in both cell lines and primary patient samples. In contrast, several drug classes, including glucocorticoids and tyrosine kinase inhibitors such as dasatinib, inhibited NK-cell cytotoxicity. Single-cell RNA sequencing revealed drug-induced transcriptomic changes in both NK and target CML cells. SMAC mimetics upregulated NF-κB target genes in NK cells, potentially contributing to their enhanced cytotoxicity. Inhibitory drugs dexamethasone, dasatinib, and sotrastaurin prevented NK-cell transition to an activated state and suppressed the expression of interferon gamma (IFN-γ) by NK cells, thus preventing IFN-γ–mediated target cell transcriptomic response. In conclusion, we discovered that SMAC mimetics sensitize cancer cells to NK-cell–mediated killing, with potential clinical applications especially in patients with advanced phase CML.
Article Details
Authors (19)
Petra Nygrén
1Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Jonas Bouhlal
1Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Emmi Jokinen
1Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Sofia Forstén
1Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
Essi Laajala
1Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Diogo Dias
1Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Shady Adnan-Awad
1Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Aleksandr Ianevski
Jay Klievink
1Hematology Research Unit Helsinki, University of Helsinki, and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Hanna Lähteenmäki
1Hematology Research Unit Helsinki, University of Helsinki, and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Heikki Kuusanmäki
Mikko Myllymäki
5Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Tiina Kasanen
1Hematology Research Unit Helsinki, University of Helsinki, and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Khalid Saeed
Dean A. Lee
Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital
Henrik Hjorth-Hansen
1St Olavs hospital HF, Hematology, Trondheim, Norway
Tero Aittokallio
Olli Dufva
1Hematology Research Unit Helsinki, University of Helsinki, and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Satu Mustjoki