Group Fredrik Bergh Thorén

Research summary

In the Thorén lab we have a broad interest in NK cell biology. The research group comprises a mix of clinical and preclinical scientists and our research activities range from projects aiming at identifying novel NK cell receptor ligands to clinical immunotherapy trials. Our research interests can be divided into two major entities; myeloid leukemias and inflammatory diseases.

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 shapes the repertoire of her/his NK cell population, and a central hypothesis of the Thoren lab has been that the NK cell repertoire impacts on the clinical outcome of patients with myeloid leukemia. Based on clinical data collected within the Re:Mission trial, our recent studies in this area have resulted in a number of publications, e.g. Bernson et al. Leukemia 2017, Bernson et al. Cancer Immunol Res. 2018, Hallner et al. Blood, 2019.

Building on our experience in AML, we have started to characterize the interplay between NK cells and leukemic blasts from patients with chronic myeloid leukemia. By using “multi-omics” approaches, we are trying to determine the genetic and proteomic signature of leukemic stem cells.

The aim of these studies is to identify novel signature markers that may be exploited in future therapeutic approaches. We are also investigating to what extent leukemic stem cells and progenitors carry ligands to NK cell receptors, which would allow them to be eradicated by NK cells.

Along these lines we have recently (Q2, 2019) initiated a phase I/II clinical trial evaluating the feasibility of combining NK cell-stimulatory immunotherapy with tyrosine kinase inhibitors. The primary objective of this trial is safety, but secondary objectives comprise studies of immune activation and clinical response in terms of reduced bcr/abl1 levels.

Inflammation

The group has had a long-lasting interest in the crosstalk between NK cells and neutrophils. Neutrophils are the most abundant leukocyte in peripheral blood and rapidly accumulate at sites of infection or tissue injury. Still, neutrophils are commonly overlooked by immunologists, considered to be unspecific solitary killers with limited interaction with other immune cells.

However, a growing body of evidence suggests that neutrophils are important initiators of immune responses of various types. 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.

Interestingly, to a rather 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, NK cells and neutrophils and other granulocytes participate in a multi-faceted crosstalk, which may modulate the immune response in different ways (see e.g Thoren et al, JI 2012, Riise et al, JI 2015, Pesce et al. Frontiers Immunol, 2018).

In the lab, we are trying to dissect the neutrophil-NK cell crosstalk under inflammatory conditions. Interesting findings include that neutrophils display a dynamic modulation of their expression of NK cell receptor ligands and that inflammatory exudates contain considerable amounts of certain soluble NK receptor ligands. We are addressing the functional consequences of these findings in ongoing studies.

Novel NK cell receptor ligands

Most NK cell receptors that regulate NK cell effector functions have already identified ligands. However, there are reasons to believe that there ligands that remain to be identified, especially for NKp46, which hitherto lacks an endogenously expressed ligand.

We have previously reported that neutrophils express an endogenous ligand to NKp46 (Thoren et al, JI, 2012). An intriguing possibility is that we can use defined, purified granule preparations obtained by subcellular fractionation for different ligand identification strategies.

In addition, we are performing CRISPR gene editing of traditional NK cell target cell lines to pinpoint the role of specific ligands and to generate edited cell lines where “novel” receptor-ligand interactions become central players for NK cell recognition.

Current group members

Fredrik Bergh Thorén, group leader, Orcid
Erna Islamagic, PhD, Postdoc
Linnea Kristensson, PhD, Postdoc
Lovisa Wennström, MD, PhD
Olle Werlenius, MD, PhD
Anne Wöhr, PhD student
Chiara Badami, PhD student

Selected publications

1. Deletion of the TMEM30A gene enables leukemic cell evasion of NK cell cytotoxicity.
   Kristenson L, Badami C, Ljungberg A, Islamagic E, Tian Y, Xie G, Hussein BA, Pesce S, Tang KW, Thorén FB. Proc Natl Acad Sci U S A. 2024 Apr 9;121(15):e2316447121. doi: 10.1073/pnas.2316447121. Epub 2024 Apr 1.PMID: 38557174 
    
2. NKG2A gene variant predicts outcome of immunotherapy in AML and modulates the repertoire and function of NK cells.
   Hussein BA, Kristenson L, Pesce S, Wöhr A, Tian Y, Hallner A, Brune M, Hellstrand K, Tang KW, Bernson E, Thorén FB. J Immunother Cancer. 2023 Aug;11(8):e007202. doi: 10.1136/jitc-2023-007202.PMID: 37648262 
    
3. The HLA-B -21 dimorphism impacts on NK cell education and clinical outcome of immunotherapy in acute myeloid leukemia.
   Hallner A, Bernson E, Hussein BA, Ewald Sander F, Brune M, Aurelius J, Martner A, Hellstrand K, Thoren FB. Blood 2019, 133:1479-1488S
    
4. Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2-Based Immunotherapy in Acute Myeloid Leukemia.
   Bernson E, Hallner A, Sander FE, Nicklasson M, Nilsson MS, Christenson K, Aydin E, Liljeqvist JA, Brune M, Foa R, Aurelius J, Martner A, Hellstrand K, Thoren FB. Cancer Immunol Res 2018, 6:1110-1119.
    
5. 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.

More group Bergh Thorén publications on PubMed