The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses

Christiansson, Lisa; Söderlund, Stina; Mangsbo, Sara M.; Hjorth‐Hansen, Henrik; Höglund, Martin; Markevärn, Berit; Richter, Johan; Stenke, Leif; Mustjoki, Satu; Loskog, Angelica; Olsson‐Strömberg, Ulla

doi:10.1158/1535-7163.mct-14-0849

Cited by 64 publications

(62 citation statements)

References 37 publications

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“…This complex crosstalk in CRC, we propose, can be investigated by implementing a combination of sophisticated informatics, -omics technologies and in vivo studies in a spatio-temporal manner, coupled with larger protein tracking and interaction studies. Emerging multiplexed technologies such as SOMAmer 1 [170], proximity extension assays [35,171] and/or SureFire 1 assays [172] will be crucial in the coming years to perform more elaborate experiments in order to elucidate complex cell signaling behaviors within a matrix of different pathways and the crosstalk between them. It is crucial to remember that in cancer and various diseases, we cannot study these pathways in isolation but instead must transition into a matrix-oriented systems approach that more comprehensively models the spatio-temporal ramifications of signaling activities within the complexity of living cells and tissues.…”

Section: Resultsmentioning

confidence: 99%

Transforming growth factor-β, MAPK and Wnt signaling interactions in colorectal cancer

Cheruku

Mohamedali

Cantor

et al. 2015

EuPA Open Proteomics

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Section: Resultsmentioning

confidence: 99%

Transforming growth factor-β, MAPK and Wnt signaling interactions in colorectal cancer

Cheruku

Mohamedali

Cantor

et al. 2015

EuPA Open Proteomics

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“…We observed that patients with progressive disease were significantly more likely to have a decrease in ALC during treatment than were patients with stable disease. Notably, imatinib has been shown to decrease the number of myeloid suppressor cells and improve the responsiveness of T-cells [14]. The decrease in ALC in patients with progression may be representative of a failure to generate an improved systemic T-cell response rather than a suppressive effect of treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor infiltration by these immune cells was associated with improved progression-free survival in association with KIT exon 11 mutations. More recent data suggest that tyrosine kinase inhibitors can induce a Th1-specific T-cell response [13] and reduce myeloid-derived suppressor cells, both of which are thought to promote antitumor immune activity [14]. Furthermore, imatinib therapy has been shown to enhance tumor-antigen presenting cell function [15].…”

Section: Introductionmentioning

confidence: 99%

Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies

Reilley¹,

Bailey²,

Subbiah³

et al. 2017

j. immunotherapy cancer

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BackgroundImatinib mesylate can induce rapid tumor regression, increase tumor antigen presentation, and inhibit tumor immunosuppressive mechanisms. CTLA-4 blockade and imatinib synergize in mouse models to reduce tumor volume via intratumoral accumulation of CD8+ T cells. We hypothesized that imatinib combined with ipilimumab would be tolerable and may synergize in patients with advanced cancer.MethodsPrimary objective of the dose-escalation study (3 + 3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose. Secondary objectives included evaluation of antitumor activity of the combination based on KIT mutation status and the capacity of tumor-associated immune biomarkers to predict response.ResultsThe primary objective to establish the maximum tolerated dose (MTD) was achieved, and the recommended phase II doses are ipilimumab at 3 mg/kg every 3 weeks and imatinib 400 mg twice daily. Of the 35 patients treated in the escalation and GIST expansion, none experienced dose-limiting toxicities. The most common grade 1/2–related adverse events (AEs) were fatigue (66%), nausea (57%), anorexia, vomiting (each 31%), edema (29%), and anemia, diarrhea, and rash (each 23%). Grade 3 AEs occurred in 6 patients (17%) and included fatigue, anemia, fever, rash, and vomiting. There were no grade 4 AEs. In general, the combination was well tolerated. Among all patients, 2 responses were seen: 1 partial response (GIST) and 1 partial response (melanoma). Stable disease was seen in 6 patients lasting an average of 6 months. The melanoma responder was KIT mutated and the GIST responder was wild-type.ConclusionsOur findings suggest that this combination of a targeted agent with checkpoint blockade is safe across multiple tumor types. Low activity with no clear signal for synergy was observed in escalation or GIST expansion cohorts. Assessment of antitumor activity of this combination in the KIT-mutant melanoma population is being evaluated.Trial registrationClinicaltrials.gov NCT01738139, registered 28 November 2012.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-017-0238-1) contains supplementary material, which is available to authorized users.

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“…The sequence of administration of immune treatment and targeted therapy is important. In addition, mRCC patients, who discontinued the treatment of PD-1 inhibitor either in monotherapy or combined with CTLA-4 inhibitor/VEGFR-TKI, could still get the benefits from subsequent VEGFR-TKI therapy without increase of toxicity [7]. Accumulating evidence suggests that RCC is amenable to immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Suppression of immune regulatory cells with combined therapy of celecoxib and sunitinib in renal cell carcinoma

et al. 2016

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ObjectiveTo observe the the potential benefit of sunitinib in combination with cyclooxygenase-2(COX-2) inhibitor in renal cell carcinoma therapy.Methods769-p cell lines were treated with sunitinib, celecoxib, or in combination at different concentrations respectively. We investigated the expression of granulocyte-macrophage colony stimulating factor (GM-CSF) in 769-p and cell proliferation in vitro. BALB/c mice implanted with Renca cells were divided into 4 groups and administered orally by gavage with sunitinib, COX-2 inhibitor (celecoxib) monotherapy or combination, and PBS respectively. Tumor growth and animal survival were observed. The myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in peripheral blood and spleen were determined by flow cytometry. The MDSCs protein was extracted for STAT3 analysis by western blot.Results769-p cell lines were suppressed in a dose and time-dependent manner. The expression of GM-CSF was substantially inhibited by celecoxib and sunitinib. Combination of sunitinib and celecoxib in vivo could effectively reduce the MDSCs than those in control group. Meanwhile, the CD4+ lymphocytes were strongly increased and the expression of signal transducer and activator of transcription 3 (STAT3) in MDSCs were significantly reduced.ConclusionCombination therapy with sunitinib and celecoxib intensified the curative effects to renal cell carcinoma by suppressing immune regulatory cells.

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The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses

Cited by 64 publications

References 37 publications

Transforming growth factor-β, MAPK and Wnt signaling interactions in colorectal cancer

Transforming growth factor-β, MAPK and Wnt signaling interactions in colorectal cancer

Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies

Suppression of immune regulatory cells with combined therapy of celecoxib and sunitinib in renal cell carcinoma

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