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Myeloid-Derived Suppressor Cells and Other Immune Escape Mechanisms in Chronic Leukemia
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.
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 [en]
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: urn:nbn:se:uu:diva-197604ISBN: 978-91-554-8630-3 (print)OAI: oai:DiVA.org:uu-197604DiVA: diva2:613700
Public defence
2013-05-17, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-04-25 Created: 2013-03-30 Last updated: 2013-08-30Bibliographically approved
List of papers
1. Increased Level of Myeloid-Derived Suppressor Cells, Programmed Death Receptor Ligand 1/Programmed Death Receptor 1, and Soluble CD25 in Sokal High Risk Chronic Myeloid Leukemia
Open this publication in new window or tab >>Increased Level of Myeloid-Derived Suppressor Cells, Programmed Death Receptor Ligand 1/Programmed Death Receptor 1, and Soluble CD25 in Sokal High Risk Chronic Myeloid Leukemia
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, e55818- p.Article in journal (Refereed) Published
Abstract [en]

Immunotherapy (eg interferon α) in combination with tyrosine kinase inhibitors is currently in clinical trials for treatment of chronic myeloid leukemia (CML). Cancer patients commonly have problems with so called immune escape mechanisms that may hamper immunotherapy. Hence, to study the function of the immune system in CML is of interest. In the present paper we have identified immune escape mechanisms in CML with focus on those that directly hamper T cells since these cells are important to control tumor progression. CML patient samples were investigated for the presence of myeloid-derived suppressor cells (MDSCs), expression of programmed death receptor ligand 1/programmed death receptor 1 (PD-L1/PD-1), arginase 1 and soluble CD25. MDSC levels were increased in samples from Sokal high risk patients (p<0,05) and the cells were present on both CD34 negative and CD34 positive cell populations. Furthermore, expression of the MDSC-associated molecule arginase 1, known to inhibit T cells, was increased in the patients (p = 0,0079). Myeloid cells upregulated PD-L1 (p<0,05) and the receptor PD-1 was present on T cells. However, PD-L1 blockade did not increase T cell proliferation but upregulated IL-2 secretion. Finally, soluble CD25 was increased in high risk patients (p<0,0001). In conclusion T cells in CML patients may be under the control of different immune escape mechanisms that could hamper the use of immunotherapy in these patients. These escape mechanisms should be monitored in trials to understand their importance and how to overcome the immune suppression.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-196216 (URN)10.1371/journal.pone.0055818 (DOI)000314610600164 ()23383287 (PubMedID)
Available from: 2013-03-05 Created: 2013-03-05 Last updated: 2017-12-06Bibliographically approved
2. Imatinib or dasatinib treatment of chronic myeloid leukemia reduces circulating myeloid-derived suppressor cells but increases their CD40 expression
Open this publication in new window or tab >>Imatinib or dasatinib treatment of chronic myeloid leukemia reduces circulating myeloid-derived suppressor cells but increases their CD40 expression
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-197601 (URN)
Available from: 2013-03-30 Created: 2013-03-30 Last updated: 2013-08-30
3. A Comparison of Multiplex Platforms for Absolute and Relative Protein Quantification
Open this publication in new window or tab >>A Comparison of Multiplex Platforms for Absolute and Relative Protein Quantification
(English)Manuscript (preprint) (Other academic)
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:uu:diva-197603 (URN)
Available from: 2013-03-30 Created: 2013-03-30 Last updated: 2013-08-30
4. T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with B-cell malignancies
Open this publication in new window or tab >>T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with B-cell malignancies
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2010 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 131, no 3, 371-376 p.Article in journal (Refereed) Published
Abstract [en]

Interleukin-2 (IL-2) is one of the most studied cytokines driving T-cell proliferation, activation and survival. It binds to the IL-2 receptor consisting of three chains, the alpha (CD25), beta and common gamma (gammac). The binding of the CD25 chain to IL-2 is necessary to expose high-affinity binding sites for the beta and gammac chains, which, in turn, are responsible for downstream signalling. A high level of soluble CD25 (sCD25) has been associated with a poor prognosis in patients with non-Hodgkin's lymphoma. The function and source of origin of this soluble receptor is not well investigated. In the present study we hypothesized that T regulatory (Treg) cells may release CD25 to act as a decoy receptor for IL-2, thereby depriving T-effector cells of IL-2. Peripheral blood from patients with B-cell malignancies (n = 26) and healthy controls (n = 27) was investigated for the presence and function of FoxP3(+) Treg cells and sCD25 by multi-colour flow cytometry and enzyme-linked immunosorbent assay. Further, the proliferative capacity of T cells was evaluated with or without the presence of recombinant sCD25. The results demonstrate that Treg cells from patients had lower CD25 expression intensity and that they released CD25 in vitro. Further, high levels of Treg cells correlated with sCD25 plasma concentration. Recombinant sCD25 could suppress T-cell proliferation in vitro. In conclusion, the release of sCD25 by Treg cells may be a mechanism to deprive IL-2 and thereby inhibit anti-tumour T-cell responses.

Keyword
B-cell malignancy, CD25, interleukin-2 receptor α, immune escape mechanism, T regulatory cell
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-128828 (URN)10.1111/j.1365-2567.2010.03308.x (DOI)000282690500008 ()20518821 (PubMedID)
Available from: 2010-07-26 Created: 2010-07-26 Last updated: 2017-12-12Bibliographically approved

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