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Imatinib or dasatinib treatment of chronic myeloid leukemia reduces circulating myeloid-derived suppressor cells but increases their CD40 expression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
Dept of Hematology St Olavs hospital, Dept of Cancer Research and Molecular Medicine, Norweigan University of Science and Technology, Trondheim, Norway.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-197601OAI: oai:DiVA.org:uu-197601DiVA: diva2:613667
Available from: 2013-03-30 Created: 2013-03-30 Last updated: 2013-08-30
In thesis
1. Myeloid-Derived Suppressor Cells and Other Immune Escape Mechanisms in Chronic Leukemia
Open this publication in new window or tab >>Myeloid-Derived Suppressor Cells and Other Immune Escape Mechanisms in Chronic Leukemia
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, a minute chromosome that leads to the creation of the fusion gene BCR/ABL and the transcription of the fusion protein BCR/ABL in transformed cells. The constitutively active tyrosine kinase BCR/ABL confers enhanced proliferation and survival on leukemic cells. CML has in only a few decades gone from being a disease with very bad prognosis to being a disease that can be effectively treated with oral tyrosine kinase inhibitors (TKIs). TKIs are drugs inhibiting BCR/ABL as well as other tyrosine kinases. In this thesis, the focus has been on the immune system of CML patients, on immune escape mechanisms present in untreated patients and on how these are affected by TKI therapy. We have found that newly diagnosed, untreated CML patients exert different kinds of immune escape mechanisms. Patients belonging to the Sokal high-risk group had higher levels of myeloid-derived suppressor cells (MDSCs) as well as high levels of the programmed death receptor 1 (PD-1)-expressing cytotoxic T cells compared to control subjects. Moreover, CML patients had higher levels of myeloid cells expressing the ligand for PD-1, PD-L1. CML patients as well as patients with B cell malignacies had high levels of soluble CD25 in blood plasma. In B cell malignacies, sCD25 was found to be released from T regulatory cells (Tregs). Treatment with the TKIs imatinib or dasatinib decreased the levels of MDSCs in peripheral blood. Tregs on the other hand increased during TKI therapy. The immunostimulatory molecule CD40 as well as NK cells increased during therapy, indicating an immunostimulatory effect of TKIs. When evaluating immune responses, multiplex techniques for quantification of proteins such as cytokines and chemokines are becoming increasingly popular. With these techniques a lot of information can be gained from a small sample volume and complex networks can be more easily studied than when using for example the singleplex ELISA. When comparing different multiplex platforms we found that the absolute protein concentration measured by one platform rarely correlated with the absolute concentration measured by another platform. However, relative quantification was better correlated.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 882
Keyword
chronic myeloid leukemia, myeloid-derived suppressor cells, sCD25, tyrosine kinase inhibitors, multiplex protein quantification
National Category
Immunology in the medical area Cancer and Oncology Hematology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-197604 (URN)978-91-554-8630-3 (ISBN)
Public defence
2013-05-17, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Supervisors
Available from: 2013-04-25 Created: 2013-03-30 Last updated: 2013-08-30Bibliographically approved

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Christiansson, LisaSimonsson, BengtLoskog, Angelica S I

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