| 1. |
- Wennerberg, Erik, et al.
(author)
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Human anaplastic thyroid carcinoma cells are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract NK cells
- 2014
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In: Clinical Cancer Research. - 1078-0432. ; 20:22, s. 5733-5744
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Journal article (peer-reviewed)abstract
- PURPOSE: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive forms of cancer with no curative therapies available. To date, strategies to target ATC by immunotherapy have not been evaluated. We investigated whether ATC would be a suitable target for natural killer (NK) cell-based immunotherapy.EXPERIMENTAL DESIGN: We first established seven new cell lines from ATC tumors, three from papillary thyroid carcinoma tumors and analyzed them together with eight additional ATC cell lines. Cells were analyzed for sensitivity to lysis by NK cells and their ability to chemoattract and regulate the activity of NK cells. In addition, fresh tumor samples and peripheral blood from six patients with ATC were analyzed for NK cell infiltration and phenotype.RESULTS: We observed that ATC cell lines are sensitive to lysis by ex vivo expanded NK cells and that the lysis was abrogated upon blockade of NKG2D. Sensitivity of thyroid cancer cell lines to NK cell-mediated lysis correlated with surface expression of UL16-binding protein 2 on tumor cells. Moreover, ATC cell lines produced high levels of CXCL10 and stimulated migration of expanded NK cells and ATC tumors were enriched for NK cells expressing the cognate chemokine receptor CXCR3. However, compared with NK cells in peripheral blood, ATC tumor-derived NK cells displayed a suppressed phenotype with a downregulated expression of NKG2D. In vitro, suppression of NK cell-mediated lysis and NKG2D expression by ATC cells was restored upon neutralization of prostaglandin-E2.CONCLUSIONS: ATC cell lines are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract CXCR3-positive NK cells. Patients with ATC may benefit from NK cell-based immunotherapy.
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| 2. |
- Anderud, Jonas, et al.
(author)
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Guided bone augmentation using a ceramic space-maintaining device
- 2014
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In: Oral surgery, oral medicine, oral pathology and oral radiology. - : Elsevier. - 2212-4403 .- 2212-4411. ; 118:5, s. 532-538
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Journal article (peer-reviewed)abstract
- Objective. The purpose of this study was to evaluate 3-dimensionally whether vertical bone augmentation can be achieved using a hollow hydroxyapatite space-maintaining device in a rabbit calvarial model. Furthermore, different inner surface topographies, different permeabilities, and different porosities of the ceramic were tested to determine the optimal conditions for bone regeneration.
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| 3. |
- Bougas, Kostas, et al.
(author)
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Bone apposition to laminin-1 coated implants : Histologic and 3D evaluation
- 2013
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In: International Journal of Oral and Maxillofacial Surgery. - : Elsevier BV. - 0901-5027 .- 1399-0020. ; 42:5, s. 677-682
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Journal article (peer-reviewed)abstract
- Laminin-1 has been reported as one of the factors responsible for the nucleation of calcium phosphates and, in vitro, has been reported to selectively recruit osteoprogenitors. This article focused on its in vivo effects, and evaluated the effect of laminin-1 local application on osseointegration. Polished cylindrical hydroxyapatite implants were coated with laminin-1 (test) and the bone responses in the rabbit tibiae after 2 and 4 weeks were evaluated and compared to the non-coated implants (control). Before the samples were processed for histological sectioning, they were three-dimensionally analysed with micro computed tomography (μCT). Both evaluation methods were analysed with regards to bone area around the implant and bone to implant contact. From the histologic observation, new bone formation around the laminin-1 coated implant at 2 weeks seemed to have increased the amount of supporting bone around the implant, however, at 4 weeks, the two groups presented no notable differences. The two-dimensional and three-dimensional morphometric evaluation revealed that both histologic and three-dimensional analysis showed some tendency in favour of the test group implants, however there was no statistical significance between the test and control group results.
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| 4. |
- Evans Axelsson, Susan, et al.
(author)
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Targeting free prostate-specific antigen for in vivo imaging of prostate cancer using a monoclonal antibody specific for unique epitopes accessible on free prostate-specific antigen alone
- 2012
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In: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 27:4, s. 243-251
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Journal article (peer-reviewed)abstract
- This study investigated the feasibility of targeting the free, unbound forms of prostate-specific antigen (fPSA) for in vivo imaging of prostate adenocarcinomas (PCa), as PSA is produced and secreted at abundance during every clinical stage and grade of PCa, including castration-resistant disease. We injected 125I-labeled monoclonal antibody PSA30 (specific for an epitope uniquely accessible on fPSA alone) intravenously in male nude mice carrying subcutaneous xenografts of LNCaP tumors (n=36). Mice were sacrificed over a time course from 4 hours to 13 days after injecting 125I-labeled PSA30. Tissue uptake of 125I-PSA30 at 48 and 168 hours after intravenous injection was compared with two clinically used positron emission tomography radiopharmaceuticals, 18F-fluoro-deoxy-glucose (18F-FDG) or 18F-choline, in cryosections using Digital AutoRadiography (DAR) and also compared with immunohistochemical staining of PSA and histopathology. On DAR, the areas with high 125I-PSA30 uptake corresponded mainly to morphologically intact and PSA-producing LNCaP cells, but did not associate with the areas of high uptake of either 18F-FDG or 18F-choline. Biodistribution of 125I-PSA30 measured in dissected organs ex vivo during 4 to 312 hours after intravenous injection demonstrated maximum selective tumor uptake 24–48 hours after antibody injection. Our data showed selective uptake in vivo of a monoclonal antibody highly specific for fPSA in LNCaP cells. Hence, in vivo imaging of fPSA may be feasible with putative usefulness in disseminated PCa.
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| 5. |
- Magnusson, Sofia E, et al.
(author)
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Dysregulated Fc receptor function in active rheumatoid arthritis
- 2014
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In: Immunology Letters. - : Elsevier BV. - 0165-2478 .- 1879-0542. ; 162:1 Pt A, s. 200-206
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Journal article (peer-reviewed)abstract
- Given the critical role of Fc gamma receptors (FcgammaR) as primary targets for autoantibody-mediated effects an important issue is how the FcgammaR pathway is affected in autoimmune disorders. Here we investigated the FcgammaR function in monocytes from rheumatoid arthritis (RA) patients in relation to immunoglobulin levels and disease activity. Peripheral blood was obtained from 30 RA patients with clinical acute joint synovitis (active RA), 28 RA patients with no clinical signs of acute joint synovitis (non-active RA) and 34 healthy controls. Prior the functional studies the monocytes were characterized of their FcgammaRI (CD64), II (CD32), IIb (CD32b) and III (CD16) expression as well as their cell surface bound IgG. The monocytic FcgammaR function was assessed by binding of human IgG1 and IgG3 immune complexes (IC) and TNF secretion in vitro. IgG anti-citrullinated peptide antibodies (ACPA) were analyzed in the plasma. We found that monocytes from active RA patients had increased levels of FcgammaRI, II and cell surface IgG concurrently with impaired FcgammaR function. This was evident by reduced IgG1-IC binding and decreased TNF secretion in response to IgG3-IC. In contrast, monocytes from non-active RA patients displayed a normal FcgammaR function and had increased FcgammaRIIb expression together with elevated FcgammaRI, II and cell surface IgG. The ACPA levels did not differ in active and non-active RA patients but correlated with the monocytic FcgammaRIII expression in the patients. In conclusion, active RA patients display a dysregulated FcgammaR function that may represent a novel phenotypic and likely pathogenetic marker for active RA. A disease and FcgammaR function controlling effect is suggested by the increased inhibitory FcgammaRIIb in non-active RA.
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| 6. |
- Sarhan, Dhifaf, et al.
(author)
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A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells
- 2013
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In: Cancer Immunology, Immunotherapy. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1432-0851 .- 0340-7004.
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Journal article (peer-reviewed)abstract
- The proteasome inhibitor bortezomib simultaneously renders tumor cells sensitive to killing by natural killer (NK) cells and resistant to killing by tumor-specific T cells. Here, we show that b-AP15, a novel inhibitor of proteasome deubiquitinating activity, sensitizes tumors to both NK and T cell-mediated killing. Exposure to b-AP15 significantly increased the susceptibility of tumor cell lines of various origins to NK (p<0.0002) and T cell (p=0.02) –mediated cytotoxicity. Treatment with b-AP15 resulted in increased TRAIL [tumor necrosis factor-related apoptosis-inducing ligand] receptor-2 expression (p=0.03) and decreased cFLIP expression in tumor cells in vitro. In tumor-bearing SCID/Beige mice, treatment with b-AP15 followed by infusion of either human NK cells or tumor-specific T cells resulted in a significantly delayed tumor progression compared with mice treated with NK cells (p=0.006), T cells (p<0.0001), or b-AP15 alone (p=0.003). Combined infusion of NK and T cells in tumor-bearing BALB/c mice following treatment with b-AP15 resulted in a significantly prolonged long-term survival compared with mice treated with b-AP15 and NK or T cells (p≤0.01). Our findings show that b-AP15-induced sensitization to TRAIL-mediated apoptosis could be used as a novel strategy to augment the anti-cancer effects of adoptively infused NK and T cells in patients with cancer.
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| 7. |
- Sarhan, Dhifaf, et al.
(author)
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Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-gamma
- 2013
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In: European Journal of Immunology. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1521-4141 .- 0014-2980.
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Journal article (other academic/artistic)abstract
- Natural killer (NK) cells are innate lymphocytes that are able to directly kill tumor cells through different mechanisms including ligation of TNF-related apoptosis-inducing ligand (TRAIL) receptors. Zoledronic acid (ZA) is a bisphosphonate known to upregulate the expression of TRAIL on human γδ T cells. Here, we investigated whether exposure to ZA would upregulate TRAIL expression on human NK cells and augment their cytotoxicity against tumor cells. When cocultured with monocytes, treatment with ZA and IL-2 resulted in a significant upregulation of TRAIL expression on human NK cells (p = 0.002). Consequently, ZA-primed NK cells were significantly more cytotoxic against TRAIL sensitive tumor cells (p < 0.0001). In the presence of ZA and IL-2, monocytes produced high levels of IFN-γ; when cultured in the presence of neutralizing antibodies to IFN-γ, TRAIL expression and TRAIL-mediated cytotoxicity of NK cells were significantly reduced. Furthermore, in tumor-bearing SCID/Beige mice, a significant delayed tumor progression and prolonged survival was observed after infusion of ZA-primed NK cells compared with that observed in mice infused with unprimed NK cells. These findings represent a novel approach to potentiate TRAIL-mediated apoptosis by adoptively infused NK cells that could improve the outcome in patients with cancer.
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| 8. |
- Wennerberg, Erik, et al.
(author)
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Doxorubicin sensitizes human tumor cells to NK and T cell-mediated killing by augmented TRAIL-receptor signaling
- 2013
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In: International Journal of Cancer. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1097-0215 .- 0020-7136.
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Journal article (other academic/artistic)abstract
- Doxorubicin (DOX) is an anthracycline antibiotic that is widely used to treat different types of malignancy. In this study, it was studied whether DOX could be used to render tumor cells susceptible to apoptosis by NK and T cells. Pretreatment with subapoptotic doses of DOX sensitized tumor cell lines of various histotypes to both NK and T cells resulting in a 3.7 to 32.7% increase in lysis (2.5 mean fold increase, p < 0.0001) and a 2.9 to 14.2% increase in lysis (3.0 mean-fold increase, p < 0.05), respectively. The sensitizing effect of the drug was primarily dependent on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-receptor signaling, but not on Fas-ligand, perforin, NKG2D or DNAM-1. The central role of the TRAIL signaling pathway was further supported by an increased expression of TRAIL-R2 on DOX-treated tumor cells and by downregulation of cellular FLICE inhibitory protein, the inhibitors of death receptor-mediated apoptosis. Compared to untreated cells, pretreatment of tumor cells with DOX showed increased processing and activation of caspase-8 on coculture with NK or T cells. The significance of this treatment strategy was confirmed using a xenogeneic tumor-bearing mouse model. Tumor progression was delayed in mice that received either NK cells (p < 0.05) or T cells (p < 0.0001) following DOX treatment compared to mice receiving either cell type alone. Moreover, combined infusion of both NK and T cells following DOX treatment not only delayed tumor progression but also significantly improved the long-term survival (p < 0.01). Based on these findings, it was proposed that DOX can be used to improve the efficacy of adoptive cell therapy in patients with cancer.
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| 9. |
- Wennerberg, Erik
(author)
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Natural killer cells in cancer : studies on migration and cytotoxicity
- 2014
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Doctoral thesis (other academic/artistic)abstract
- The role of natural killer (NK) cells in cancer development has been studied extensively over the last four decades and the increasing knowledge on NK cell regulation has improved both safety and efficacy of treatment. Despite these recent advances the clinical success has to date been modest in treatment of solid tumors, owing both to suboptimal directed migration of NK cells and the tumor cell’s resistance to NK cell-mediated lysis. This thesis focuses on strategies to overcome these critical issues thus improving the anti-tumor effect of adoptive NK cell therapy. In paper I, we have studied the sensitizing effect of doxorubicin on tumor cells to NK cell and T cell-mediated lysis. The potential clinical advantage of using doxorubicin as a preconditioning agent was highlighted in a xenograft mouse model, where mice receiving low-doses of doxorubicin prior to NK cell infusion had a stronger anti-tumor effect of a subsequent NK cell treatment compared to mice receiving only NK cell treatment. Further, we identified TRAIL-signaling as the main pathway responsible for the tumor sensitization due to decreased expression of the anti-apoptotic protein cFLIP. In paper II we have established that the cytotoxicity of NK cells can be augmented by co-culturing them with monocytes in presence of the biphosphonate zoledronic acid (ZA). We observed an upregulated expression of TRAIL on NK cells, through increased levels of monocyte-derived IFNγ in the culture. Thus, NK cells primed with ZA were able to lyse TRAIL-sensitive tumors both in vitro and in vivo. In paper III, we studied CXCL10-mediated migration of NK cells toward solid tumors. We found that ex vivo expansion of NK cells induced a 10-fold increase in CXCR3-receptor expression, which allowed them to migrate towards tumor cells in a CXCL10-dependent manner. In two separate xenograft models we could demonstrate the anti-tumor effect of CXCL10-induced migration of adoptively transferred CXCR3-positive NK cells by their selective targeting of CXCL10-producing tumors, which resulted in reduced tumor progression and prolonged survival. In paper IV, we identified anaplastic thyroid carcinoma (ATC) as a potential novel target for NK cell therapy. We found that ATC cells were sensitive to NKG2D-mediated lysis due to high expression of ULBP2 on tumor cells. In addition, tumor cells produced high levels of CXCL10 which attracted CXCR3-positive NK cells in vitro. In ATC tumor samples we found a suppressed NK cell population although enriched for CXCR3 expression suggesting that CXCL10 may have been involved in the chemoattraction of the NK cells. In conclusion, we have studied some of the important aspects of how NK cells interact with tumor cells and suggested approaches that could improve the use of NK cells in cancer therapy. Moreover, we have identified the highly aggressive tumor ATC as being uniquely sensitive to NK cell lysis and have studied the prospects of developing NK cell therapies for ATC patients.
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