Nicole Marquardt team – Human tissue-resident NK cells in homeostasis and disease
Our research focuses on the biology of human NK cells in tissues and their role in tissue-specific pathologies.
The team as part of the Petter Höglund research group at the Center for Hematology and Regenerative Medicine (HERM).
In our team, we focus primarily on Natural Killer (NK) cells in human lung (healthy, tumor-free, tumor, respiratory viral infections), but also other tissues as well as tissue-homing capacities of blood NK cells. In detail, we are interested in NK cell function and regulation in different areas of the respiratory tract and in solid tumors. Furthermore, we aim at understanding the responsiveness of tissue-resident NK cells in e.g. viral infections with influenza A virus or SARS-CoV-2.
Our vision is that our generated knowledge will be translated into development and optimization of prevention and treatment strategies for patients affected by lung cancer or respiratory viral infections.
NK cell research
Human NK cells are well-characterized in the peripheral blood, however, rather little is known about NK cells in tissues. While peripheral blood NK cells likely play an important role in hematologic malignancies, tissue-resident NK cells presumably represent a front line of defense in tissues such as the lung for example during respiratory viral infections, or play a pivotal role in the defense against solid tumors. Hence, the identification of distinct NK cell subsets homing to and residing in human tissues allows us to gain new perspectives about disease development, progression, and potential therapeutic approaches in tissue-specific pathologies.
Nicole has a long-standing expertise in the field of NK cell research both in blood and tissues. Her research focuses primarily on NK cells in tissues in homeostasis and disease.
Nicole completed her PhD in Hannover, Germany, in 2011, and got recruited to the group of Jakob Michaëlsson at the Center for Infectious Medicine (CIM) the same year. In 2018, she finished her Assistant Professor at CIM and became team leader at MedH in 2019. Early 2023, Nicole and her team joined the group of Petter Höglund at the Center for Hematology and Regenerative Medicine (HERM).
Demi is particularly focusing on the role of tissue-resident NK cells in lung cancer and respiratory viral infections such as influenza virus and SARS-CoV-2.
She received her honors degree with integrated masters (MSci) in Immunology from the University of Glasgow in 2016. She studied NK cells suppression by tumor-associated macrophages in murine models of pulmonary metastatic breast cancer, at the University of Edinburgh, completing her PhD in 2019. Later that year she joined the Team Marquardt in 2019 for her postdoctoral studies.
Nicole, also known as Nici, got recruited to the team as a PhD student in April 2022. Her main research goal is to decipher the regulation of NK cells in different areas of the human lung in health and disease like respiratory viral infections and lung cancer.
Nicole earned her Bachelor’s degree at the Medical University of Innsbruck in 2018, and her Master’s degree at Karolinska Institutet in 2020. She then worked as a Research Assistant with a focus on highly pathogenic viruses at the Robert Koch-Institute in Berlin, Germany.
Previous team members
- Pablo Clavero, Internship student (February-June 2022).
- Giampiero Valenzano, Internship student (January-July 2021).
- Kathleen Schlüter, Internship student (April-June 2021).
- Andreas von Kries, Internship/Master student (January 2020 - February 2021). Now PhD-student in the group of Adelheid Cerwenka, Mannheim, Germany.
- Marlena Scharenberg, Master student (January – October 2017).
Prevention of NK cell-induced lung tissue-damage upon severe respiratory viral infections
Severe respiratory diseases such as COVID-19 and flu are commonly associated with lung tissue-damage, partly caused by an excessive immune response. While Natural Killer (NK) cells are believed to play a crucial role in host responses towards viral infections, surprisingly little is known about human NK cell regulation in respiratory viral infections. The overall aim with this project is to identify regulatory mechanisms of human blood and lung NK cells that can be targeted for treatment of patients suffering from severe acute respiratory viral infections, ultimately balancing immune pathology and immune protection in severe respiratory viral infections.
Ongoing collaborations will provide us access to non-infected human lung tissue, lung tissue from COVID-19-infected patients as well as to peripheral blood from influenza- or SARS-CoV-2-infected patients. The combination of unique human clinical material, the ability to conduct in vitro infections with highly relevant viruses, and usage of cutting-edge technologies will be the central elements of this project.
Our vision is to define the biology of human NK cell subsets in and trafficking to the lung upon viral infection, ultimately aiming at reducing disease severity, hospitalization, and mortality.
Tissue-resident NK cells in the human lung and lung tumors
In collaboration with physicians and scientists at Karolinska University Hospitals Huddinge/Solna we collect healthy lung tissue from human organ donors as well as tumor-free tissue and lung tumors from patients undergoing surgery for suspected lung cancer. We will particularly focus on NK cell lung-homing, tumor-infiltration, tissue-residency, and cytotoxicity. Cutting-edge technologies such as high parameter flow/spectral cytometry, RNA-sequencing, and live cell-imaging are key in this project proposal.
This study is performed in close collaboration with the group of Jakob Michaelsson at the Center for Infectious Medicine (CIM).
The combination of unique human clinical material and application of cutting-edge technologies will be the central elements of this project. Our vision is to harness suitable human NK cell subsets in lung cancer, ultimately aiming at reducing disease severity, hospitalization, and mortality.
Mapping the landscape of NK cells
Lung cancer is the leading type of cancer worldwide in terms of incidence and mortality. Natural Killer (NK) cells are well known for their capacity to target and lyse tumor cells, and they are currently representing a promising tool for treatment of hematopoietic cancers. However, treatment of solid tumors including lung tumors is still in its infancy. Major limitations are inefficient trafficking of NK cells to the tumor site as well as lack of NK cell infiltration into the tumor, antigen escape mechanisms, and an immunosuppressive tumor microenvironment. While we have identified distinct NK cell subsets in the human lung in previous studies, little is known about the regulation of NK cells in the human lung and in lung tumors.
This project aims at mapping the landscape of NK cells in different areas of healthy human lung and in human lung tumors. Based on the results, we aim at harnessing and expanding the NK cell subsets most suitable for infiltrating and killing lung tumor cells for future treatment of lung cancer.
- KI funding for doctoral education (KID)
- CIMED (Awarded “Rising Star 2020”)
- Karolinska Institutet
- Stiftelsen Tornspiran
- Åke Wibergs Stiftelse
- Magnus Bergvalls Stiftelse
- Accumulation of tissue-resident natural killer cells, innate lymphoid cells, and CD8+ T cells towards the center of human lung tumors.
Brownlie D, von Kries A, Valenzano G, Wild N, Yilmaz E, Säfholm J, Al- Ameri M, Alici E, Ljunggren H-G, Schliemann I, Aricak O, Haglund de Flon F, Michaëlsson J, Marquardt N. Oncoimmunology Jul 11;12(1):2233402. 2023. PMID: 37448786.
- Comparison of Lung-Homing Receptor Expression and Activation Profiles on NK Cell and T Cell Subsets in COVID-19 and Influenza.
Brownlie D, Rødahl I, Varnaite R, Asgeirsson H, Glans H, Falck-Jones S, Vangeti S, Buggert M, Ljunggren HG, Michaëlsson J, Gredmark-Russ S, Smed-Sörensen A, Marquardt N. Front Immunol 2022;16(13):834862. 2022. PMID: 35371005.
- Expansions of adaptive-like NK cells with a tissue-resident phenotype in human lung and blood.
Brownlie D, Scharenberg M, Mold JE, Hård J, Kekäläinen E, Buggert M, Nguyen S, Wilson JN, Al-Ameri M, Ljunggren HG, Marquardt N, Michaëlsson J
Proceedings of the National Academy of Sciences Mar;118: e2016580118. 2021. PMID: 33836578.
* Shared senior authorship.
- Distinct developmental pathways from blood monocytes generate human lung macrophage diversity.
Evren E, Ringqvist E, Tripathi KP, Sleiers N, Rives IC, Alisjahbana A, Gao Y, Sarhan D, Halle T, Sorini C, Lepzien R, Marquardt N, Michaëlsson J, Smed-Sörensen A, Botling J, Karlsson MCI, Villablanca EJ, Willinger T. Immunity 54, 1-17. 2020. PMID: 33382972.
- Natural killer cell immunotypes related to COVID-19 disease severity.
Maucourant C, Filipovic I, Ponzetta A, Aleman S, Cornillet M, Hertwig L, Strunz B, Lentini A, Reinius B, Brownlie D, Cuapio A, Ask EH, Hull RM, Haroun-Izquierdo A, Schaffer M, Klingström J, Folkesson E, Buggert M, Sandberg JK, Eriksson LI, Rooyackers O, Ljunggren HG, Malmberg KJ, Michaëlsson J, Marquardt N, Hammer Q, Strålin K, Björkström NK, Sci Immunol. 5(50):eabd6832. 2020. PMID: 32826343.
- NK cells are activated and primed for skin-homing during acute dengue virus infection in humans.
Zimmer CL, Cornillet M, Solà-Riera C, Cheung KW, Ivarsson MA, Lim MQ, Marquardt N, Leo YS, Lye DC, Klingström J, MacAry PA, Ljunggren HG, Rivino L, Björkström NK. Nat Commun 10: 3897. 2019. PMID: 31467285.
- Unique transcriptional and protein-expression signature in human lung tissue-resident NK cells.
Marquardt N, Kekäläinen E, Chen P, Lourda M, Wilson JN, Scharenberg M, Bergman P, Al-Ameri M, Hård J, Mold JE, Ljunggren HG, Michaëlsson J
Nat Commun 10: 3841–12. 2019. PMID: 31451696.
- Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells.
Scharenberg M, Vangeti S, Kekäläinen E, Bergman P, Al-Ameri M, Johansson N, Sondén K, Falck-Jones S, Färnert A, Ljunggren HG, Michaëlsson J, Smed-Sörensen A, Marquardt N. Front Immunol 10: 1116. 2019. PMID: 31156653.
- CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin.
Cheuk S, Schlums H, Gallais Sérézal I, Martini E, Chiang SC, Marquardt N, Gibbs A, Detlofsson E, Introini A, Forkel M, Höög C, Tjernlund A, Michaëlsson J, Folkersen L, Mjösberg J, Blomqvist L, Ehrström M, Ståhle M, Bryceson YT, Eidsmo L
Immunity 46: 287–300. 2017. PMID: 28214226.
- Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69-CD56dim cells.
Marquardt N, Kekäläinen E, Chen P, Kvedaraite E, Wilson JN, Ivarsson MA, Mjösberg J, Berglin L, Säfholm J, Manson ML, Adner M, Al-Ameri M, Bergman P, Orre AC, Svensson M, Dahlén B, Dahlén SE, Ljunggren HG, Michaëlsson J
Allergy Clin. Immunol. 139: 1321–1330.e4. 2016. PMID: 27670241.