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Neutrophils in cancer and cancer treatment
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. (Constantin Urban)
2025 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Neutrofiler vid cancer och cancerbehandling (Swedish)
Abstract [en]

As part of innate immunity, neutrophils constitute the first line of defense against microbial infections. A low neutrophil count is a considerable risk factor for acquiring severe infections and is a common side effect for patients undergoing chemotherapy. Whether or not neutrophil function is affected by chemotherapy is still largely unknown. We evaluated the functions of neutrophils derived from the newly generated bone marrow of patients who underwent allogeneic stem cell transplantation. We sought to understand whether extended neutrophil dysfunction could add to the risk of infection. For this purpose, we assessed chemotaxis, phagocytosis, and oxidative burst using fluorescence- and luminol-based methods in neutrophils from transplanted patients. We found a decrease in chemotactic ability two weeks after neutrophil engraftment, and the lowered response only normalized at later time points. Interestingly, we observed a similar reduction in chemotactic ability in neutrophils isolated from healthy stem cell donors undergoing treatment with granulocyte-colony-stimulating factor (G-CSF) to prepare for stem cell donation, suggesting that this effect might be transferred to the newly generated neutrophils by an unknown mechanism.

Chemotherapy-free treatment against acute promyelocytic leukemia (APL) using arsenic in combination with retinoic acid has proven to be effective. One of the additional benefits is a decreased risk of neutropenia; however, to what extent the treatment affects neutrophil function remains unknown. We found that neutrophil function was altered in a compensatory manner, with increased chemotaxis at time points with decreased numbers of neutrophils.

In solid cancers, a high number of neutrophils in peripheral blood is often linked to a worse prognosis. In these instances, neutrophils frequently accumulate in the tumor microenvironment. We used a co-culture model with breast cancer cells and stromal cells to investigate the interaction between neutrophils and the tumor microenvironment. Culturing the cells together created a proinflammatory environment, much like the scenario seen in cancerous tissue. The supernatant was chemoattractive to neutrophils from healthy donors and activated them to produce reactive oxygen species. When neutrophils were added to the co-culture model, using Seahorse analysis, we observed a shift in the metabolic pattern of the co-culture, creating an increase in mitochondrial function. We conclude that the increased mitochondrial activity indicates a protumorigenic effect exerted by neutrophils.In summary, neutrophil function in patients with hematological diseases is altered due to treatment and could contribute to patients' susceptibility to infection. Neutrophils alter the metabolism of cells in a cancer fibroblast co-culture, favoring the tumor cells, suggesting that neutrophils might be a promising target for future anticancer treatment.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2025. , p. 64
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2342
Keywords [en]
neutrophil, chemotaxis, tumor microenvironment, tumor cell metabolism, cancer, G-CSF, allogeneic transplantation, acute promyelocytic leukemia
National Category
Hematology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-234107ISBN: 978-91-8070-592-9 (print)ISBN: 978-91-8070-593-6 (electronic)OAI: oai:DiVA.org:umu-234107DiVA, id: diva2:1927595
Public defence
2025-02-14, Hörsal D, by 1D, plan 9, Umeå Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2025-01-24 Created: 2025-01-15 Last updated: 2025-01-16Bibliographically approved
List of papers
1. Assessment of Neutrophil Chemotaxis Upon G-CSF Treatment of Healthy Stem Cell Donors and in Allogeneic Transplant Recipients
Open this publication in new window or tab >>Assessment of Neutrophil Chemotaxis Upon G-CSF Treatment of Healthy Stem Cell Donors and in Allogeneic Transplant Recipients
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2018 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 9, article id 1968Article in journal (Refereed) Published
Abstract [en]

Neutrophils are crucial for the human innate immunity and constitute the majority of leukocytes in circulation. Thus, blood neutrophil counts serve as a measure for the immune system's functionality. Hematological patients often have low neutrophil counts due to disease or chemotherapy. To increase neutrophil counts and thereby preventing infections in high-risk patients, recombinant G-CSF is widely used as adjunct therapy to stimulate the maturation of neutrophils. In addition, G-CSF is utilized to recruit stem cells (SCs) into the peripheral blood of SC donors. Still, the actual functionality of neutrophils resulting from G-CSF treatment remains insufficiently understood. We tested the ex vivo functionality of neutrophils isolated from blood of G-CSF-treated healthy SC donors. We quantified chemotaxis, oxidative burst, and phagocytosis before and after treatment and detected significantly reduced chemotactic activity upon G-CSF treatment. Similarly, in vitro treatment of previously untreated neutrophils with G-CSF led to reduced chemotactic activity. In addition, we revealed that this effect persists in the allogeneic SC recipients up to 4 weeks after neutrophil engraftment. Our data indicates that neutrophil quantity, as a sole measure of immunocompetence in high-risk patients should be considered cautiously as neutrophil functionality might be affected by the primary treatment.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
neutrophil, granulocyte colony stimulating factor (G-CSF), allogeneic transplant, chemotaxis, hematopoietic stern cell donor
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-152255 (URN)10.3389/fimmu.2018.01968 (DOI)000444324800001 ()30254629 (PubMedID)2-s2.0-85053168114 (Scopus ID)
Funder
Västerbotten County Council
Available from: 2018-10-03 Created: 2018-10-03 Last updated: 2025-01-15Bibliographically approved
2. Arsenic treatment of acute promyelocytic leukemia affects neutrophil function in a compensatory manner
Open this publication in new window or tab >>Arsenic treatment of acute promyelocytic leukemia affects neutrophil function in a compensatory manner
2024 (English)In: Translational Medicine Communications, E-ISSN 2396-832X, Vol. 9, no 1, article id 3Article in journal (Refereed) Published
Abstract [en]

Background: Arsenic (ATO) and retinoic acid (ATRA) are successfully used as chemotherapy-free regimens to treat acute APL. Compared to traditional chemotherapy approaches, this therapy evokes fewer haematological side effects, such as severe neutropenia and thrombocytopenia, but little is known about the impact of the treatment on neutrophil function.

Methods: We included three patients undergoing consolidation treatment for APL. To evaluate the functionality of neutrophils, we assessed chemotaxis, ROS production, and neutrophil extracellular trap (NET) release during different time points of the treatment and compared them with neutrophils from healthy donors.

Results: We revealed that the chemotactic ability of neutrophils isolated from APL patients was decreased before starting each cycle of treatment. However, there was an increase in chemotactic ability in the first week of treatment compared to other time points. Additionally, we observed increased ROS production at the start of the treatment cycle. In vitro exposure of isolated neutrophils from healthy donors to ATO led to decreased chemotaxis at high ATO concentrations exceeding those achieved in vivo, while ROS production was not affected. Chemotaxis and ROS production were not altered by exposure to ATRA in vitro and neither ATO nor ATRA had an effect on neutrophils’ ability to release NETs.

Conclusions: Our study suggests that ATO and ATRA therapy alter neutrophil function by increasing chemotaxis and reducing ROS production. The effect on neutrophil function does not, however, seem to impact infection susceptibility in our patients, indicating that the enhanced functionality might compensate for the lowered neutrophil count.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
Neutrophils, Acute promyelocytic leukemia, Chemotaxis, Arsenic, Infection risk assessment
National Category
Hematology
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-234103 (URN)10.1186/s41231-024-00162-2 (DOI)
Funder
Swedish Research Council, 2020-01764Swedish Research Council, 2022-00850
Available from: 2025-01-15 Created: 2025-01-15 Last updated: 2025-01-15Bibliographically approved
3. Interaction of neutrophils with breast cancer cells and fibroblast in a co-culture model
Open this publication in new window or tab >>Interaction of neutrophils with breast cancer cells and fibroblast in a co-culture model
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-234106 (URN)
Available from: 2025-01-15 Created: 2025-01-15 Last updated: 2025-01-16Bibliographically approved

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Thunström Salzer, Anna

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