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The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
St Olavs Hosp, Dept Hematol, Trondheim, Norway.;Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Trondheim, Norway..
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2015 (English)In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 14, no 5, 1181-1191 p.Article in journal (Refereed) Published
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Text
Abstract [en]

Immune escape mechanisms promote tumor progression and are hurdles of cancer immunotherapy. Removing immunosuppressive cells before treatment can enhance efficacy. Tyrosine kinase inhibitors (TKI) may be of interest to combine with immunotherapy, as it has been shown that the inhibitor sunitinib reduces myeloid suppressor cells in patients with renal cell carcinoma and dasatinib promotes expansion of natural killer-like lymphocytes in chronic myeloid leukemia (CML). In this study, the capacity of dasatinib and imatinib to reduce myeloid suppressor cells and to induce immunomodulation in vivo was investigated ex vivo. Samples from CML patients treated with imatinib (n = 18) or dasatinib (n = 14) within a Nordic clinical trial (clinicalTrials.gov identifier: NCT00852566) were investigated for the presence of CD11b(+)CD14(-)CD33(+) myeloid cells and inhibitorymolecules (arginase I, myeloperoxidase, IL10) as well as the presence of natural killer cells, T cells (naive/memory), and stimulatory cytokines (IL12, IFN gamma, MIG, IP10). Both imatinib and dasatinib decreased the presence of CD11b(+)CD14(-)CD33(+) myeloid cells as well as the inhibitory molecules and the remaining myeloid suppressor cells had an increased CD40 expression. Monocytes also increased CD40 after therapy. Moreover, increased levels of CD40, IL12, natural killer cells, and experienced T cells were noted after TKI initiation. The presence of experienced T cells was correlated to a higher IFNg and MIG plasma concentration. Taken together, the results demonstrate that both imatinib and dasatinib tilted the immunosuppressive CML tumor milieu towards promoting immune stimulation. Hence, imatinib and dasatinib may be of interest to combine with cancer immunotherapy. 

Place, publisher, year, edition, pages
2015. Vol. 14, no 5, 1181-1191 p.
National Category
Hematology Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-269778DOI: 10.1158/1535-7163.MCT-14-0849ISI: 000358053000010PubMedID: 25761894OAI: oai:DiVA.org:uu-269778DiVA: diva2:885414
Available from: 2015-12-18 Created: 2015-12-18 Last updated: 2017-12-01Bibliographically approved
In thesis
1. Clinical and Immunological Studies in Chronic Myeloid Leukaemia
Open this publication in new window or tab >>Clinical and Immunological Studies in Chronic Myeloid Leukaemia
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic myeloid leukaemia (CML) is characterised by the constitutively active tyrosine kinase BCR-ABL. Standard treatment with tyrosine kinase inhibitors (TKI) in the chronic phase (CP) of CML conveys excellent long-term prognosis but is associated with side effects and costs. Treatment free remission (TFR) is possible in a proportion of patients discontinuing treatment after obtaining deep treatment responses but it is not fully known how to select the right patients for stopping attempts. Treatment of accelerated phase (AP) and blast crisis (BC) is more complicated and the prognosis more dismal. In this thesis, we have studied factors of importance for outcome in CML patients with focus on immunological factors and clinical management.

In a cohort of 32 newly diagnosed CP-CML patients, evidence of active immune escape mechanisms were found. These declined with the course of TKI treatment and at the same time, effector lymphocyte responses were elicited. These anti-leukaemia immune responses might help in the long-term control of CML. Multiple plasma protein markers were also measured with three multiplex platforms in a smaller cohort of patients (n=14). Inflammatory cytokines and other plasma proteins were affected by TKI treatment and multiplexing seems useful for finding potential biomarkers with biologic or prognostic significance in CML.

Patients progressing to AP/BC were studied in a population-based material from the Swedish CML register. Approximately 4% of TKI-treated CP-CML patients transformed to AP/BC within 2 years of diagnosis. Monitoring of treatment responses was suboptimal in 1/3 of these patients and the median survival was 1.4 years after diagnosis of AP/BC. Thus, minimising the risk of disease progression through strict adherence to guidelines for monitoring and treatment is essential.

In a cohort of patients (n=50) discontinuing TKI treatment within a large European trial, musculoskeletal pain was reported by 30% of patients, starting within 1- 6 weeks of TKI discontinuation and spontaneously resolving over time in most cases. Patients (n=56) were also evaluated with a multiplex platform with a total of 162 inflammation- and cancer-related plasma proteins. No predictive protein biomarkers for successful TKI discontinuation could be found. However, profound effects of TKI-treatment were seen and plasma proteomics could be useful for understanding effects of long-term TKI-treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1347
Keyword
chronic myeloid leukaemia, accelerated phase, blast crisis, tyrosine kinase inhibitor, immunology, myeloid-derived suppressor cells, cytokines, proteomics, TKI discontinuation, population-based
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-324272 (URN)978-91-513-0021-4 (ISBN)
Public defence
2017-09-22, Enghoffsalen, Akademiska sjukhuset, Ingång 50, bv, Uppsala, 09:00 (English)
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Available from: 2017-09-01 Created: 2017-08-05 Last updated: 2017-09-08

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Söderlund, StinaHöglund, MartinLoskog, AngelicaOlsson-Strömberg, Ulla

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