Human tissue-resident NK cells in homeostasis and disease – Nicole Marquardt team

Our research focuses on the biology of human NK cells in tissues and their role in tissue-specific pathologies.

The team is part of the Petter Höglund research group at the Center for Hematology and Regenerative Medicine (HERM).

Our focus

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.

Projects

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

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).

Our vision

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.

Research support

  • Vetenskapsrådet
  • Cancerfonden
  • KI funding for doctoral education (KID)
  • CIMED (Awarded “Rising Star 2020”)
  • Karolinska Institutet
  • Groschinsky
  • Stiftelsen Tornspiran
  • Åke Wibergs Stiftelse
  • Magnus Bergvalls Stiftelse

Publications

Selected publications

Members and contact

Group leader

All members of the group

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).