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Group Fredrik Bergh Thorén

Research Summary

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.

Myeloid leukemia
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 afflicted by myeloid leukemia. In a recent publication (Bernson et al. Leukemia 2017), we have demonstrated that a population of autoreactive NK cells plays a key role in the prevention of relapse in acute myeloid leukemia. In further studies we aim i) to elucidate how different NK cell subsets contribute to our anti-leukemic defense during immunotherapy, and ii) to investigate to what extent leukemic stem cells carry ligands for NK cell receptors that could enable eradication of the residual leukemic cells.

Inflammation
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 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.

Group members

Fredrik Bergh Thorén, group leader, Orcid
Lovisa Wennström, MD, PhD
Elin Bernson, PhD
Michael Gabl, PhD
Olle Werlenius, MD, PhD
Brwa Ali Hussein, MD, PhD student
Hana Komic, PhD student
Magnus Hessel, MD
Malin Pasanen, MD student
Linnea Kristensson, Master student in Biotechnology

Selected Publications

  1. Impact of killer-immunoglobulin-like receptor and human leukocyte antigen genotypes on the efficacy of immunotherapy in acute myeloid leukemia.Bernson E, Hallner A, Sander FE, Wilsson O, Werlenius O, Rydström A, Kiffin R, Brune M, Foà R, Aurelius J, Martner A, Hellstrand K, Thorén FB. Leukemia. 2017 Dec;31(12):2552-2559. doi: 10.1038/leu.2017.151.
  2. Role of natural killer cell subsets and natural cytotoxicity receptors for the outcome of immunotherapy in acute myeloid leukemiaMartner A, Rydstrom A, Riise RE, Aurelius J, Anderson H, Brune M, Foà R, Hellstrand K, Thoren FB. Oncoimmunology. 2016, 5(1):e1041701.
  3. Opposing effects of immunotherapy in melanoma using multisubtype interferon-alpha – can tumor immune escape after immunotherapy accelerate disease progression?Strannegard O, Thoren FB.Oncoimmunology.2015, 5(3): e1091147
  4. TLR-Stimulated Neutrophils Instruct NK Cells To Trigger Dendritic Cell Maturation and Promote Adaptive T Cell Responses.Riise RE, Bernson E, Aurelius J, Martner A, Pesce S, Della Chiesa M, Marcenaro E, Bylund J, Hellstrand K, Moretta L, Moretta A, Thorén FB.J Immunol. 2015 Aug 1;195(3):1121-8. doi: 10.4049/jimmunol.1500709.

 

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Page Manager: Ulrika Lantz Carlsson|Last update: 3/28/2018
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