In the Thorén lab we are studying different aspects of NK cell interactions with myeloid cells. Our research interests can be divided into two major entities, myeloid leukemia and inflammatory conditions.
Work during recent years by us and others has demonstrated that natural killer (NK) cells are key effector cells in myeloid leukemia, and that NK cell-stimulatory immunotherapy may contribute to elimination of leukemic cells. Traditionally, cytotoxic NK cells have been regarded as a uniform cell type, but with novel multi-dimensional analytical instruments we have learnt that this cell type alone comprises thousands of different phenotypic populations in a given individual. The immunogenetics, infection history etc. of an individual will shape the repertoire of her/his NK cell population, and a bearing idea of the Thoren lab is that this repertoire influences the clinical outcome of patients inflicted by myeloid leukemia. In a few recent publications (Bernson et al. Leukemia 2017, Bernson et al. Cancer Immunol Res 2018, Hallner et al. Blood 2019), we have demonstrated that such aspects of NK cell biology play a key role in the prevention of relapse in acute myeloid leukemia. In further studies we will i) continue to characterize how different NK cell subsets contribute to our anti-leukemic defense during immunotherapy, and ii) investigate whether leukemic stem cells carry ligands for NK cell receptors, which could enable eradication of the residual leukemic cells. For these studies, we were invited to join the BD Multi-Omics alliance where we combine BD Ab-seq and the BD Rhapsody system to address these research issues.
We are since April 2019 enrolling patients to a phase I/II clinical trial in chronic myeloid leukemia (CML; PI: Lovisa Wennström), in which we combine tyrosine kinase inhibitors with an NK cell-stimulatory regimen comprising HDC (NOX2 inhibitor) and IL-2. The main focus of the trial is safety, but secondary objectives include studying NK cell activation and therapy-induced effects on the malignant clone. In the long run, we aim to test whether combing NK cell-stimulatory immunotherapy with tyrosine kinase inhibitors may allow patients to quit TKI therapy with maintained treatment-free remission (TFR).
Neutrophils are the most abundant leukocyte in peripheral blood and rapidly accumulate at sites of infection or tissue injury. Traditionally, neutrophils have been overlooked in immunology, considered to be unspecific solitary killers with limited interaction with other immune cells. Today, we know that neutrophils are equipped with a battery of pattern recognition receptors, such as TLRs, which recognize a wide array of pathogens. Activated neutrophils produce chemokines and cytokines that attract more neutrophils, but also other immune cells. To a large extent NK cells share chemokine receptor profiles with neutrophils, and thus NK cells soon accumulate in response to neutrophil-derived chemokines. In the inflamed tissue neutrophils and NK cells participate in a multi-faceted crosstalk, which results in more efficacious maturation of dendritic cells and influences adaptive responses (see e.g. Riise et al, JI 2015). We are currently trying to dissect the mechanisms for the neutrophil-NK cell crosstalk. We have recently discovered some novel mediators, and put in a lot of efforts to elucidate their role in inflammatory pathologies.
We do also have a long-standing interest in the role for NK cells in the resolution phase of inflammation. Neutrophils display a dynamic modulation of their expression of NK cell receptor ligands. A key hypothesis is that inflammatory neutrophils upregulate activating ligands, which confer increased susceptibility to NK cell cytotoxicity. In fact, we have previously shown that neutrophils express an endogenous ligand to NKp46 (Thoren et al, JI, 2012), a Holy Grail in NK cell biology. An intriguing possibility is that we can use defined, purified granule preparations obtained by subcellular fractionation for different ligand identification strategies. These findings have also incited us to set up additional methods to identify novel NK cell ligands on various cells, such as CRISPR screens.