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Sarha, D., Brandt, L., Felices, M., Guldevall, K., Lenvik, T., Hinderlie, P., . . . Miller, J. S. (2018). 161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS. BLOOD ADVANCES, 2(12), 1459-1469
Open this publication in new window or tab >>161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS
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2018 (English)In: BLOOD ADVANCES, ISSN 2473-9529, Vol. 2, no 12, p. 1459-1469Article in journal (Refereed) Published
Abstract [en]

Myelodysplastic syndrome (MDS) is a clonal heterogeneous stem cell disorder driven by multiple genetic and epigenetic alterations resulting in ineffective hematopoiesis. MDS has a high frequency of immune suppressors, including myeloid-derived suppressor cells (MDSCs), that collectively result in a poor immune response. MDSCs in MDS patients express CD155 that ligates the T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and delivers an inhibitory signal to natural killer (NK) cells. To mediate a productive immune response against MDS, negative regulatory checkpoints, like TIGIT, expressed on MDS NK cells must be overcome. NK cells can be directed to lyse MDS cells by bispecific killer engagers (BiKEs) that ligate CD16 on NK cells and CD33 on MDS cells. However, such CD16 x CD33 (1633) BiKEs do not induce the proliferative response in MDS NK cells needed to sustain their function. Here, we show that the addition of an NK stimulatory cytokine, interleukin-15 (IL-15), into the BiKE platform leads to productive IL-15 signaling without TIGIT upregulation on NK cells from MDS patients. Lower TIGIT expression allowed NK cells to resist MDSC inhibition. When compared with 1633 BiKE, 161533 trispecific killer engager (TriKE)-treated NK cells demonstrated superior killing kinetics associated with increased STAT5 phosphorylation. Furthermore, 161533 TriKE-treated MDS NK cells had higher proliferation and enhanced NK-cell function than 1633 BiKE-treated cells without the IL-15 linker. Collectively, our data demonstrate novel characteristics of the 161533 TriKE that support its application as an immunotherapeutic agent for MDS patients.

Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-232250 (URN)10.1182/bloodadvances.2017012369 (DOI)000436548300013 ()29941459 (PubMedID)
Funder
Swedish Foundation for Strategic Research , SBE13-0092Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20180720

Available from: 2018-07-20 Created: 2018-07-20 Last updated: 2018-07-20Bibliographically approved
Olofsson, K., Carannante, V., Ohlin, M., Frisk, T., Kushiro, K., Takai, M., . . . Wiklund, M. (2018). Acoustic formation of multicellular tumor spheroids enabling on-chip functional and structural imaging. Lab on a Chip, 18(16), 2466-2476
Open this publication in new window or tab >>Acoustic formation of multicellular tumor spheroids enabling on-chip functional and structural imaging
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2018 (English)In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 18, no 16, p. 2466-2476Article in journal (Refereed) Published
Abstract [en]

Understanding the complex 3D tumor microenvironment is important in cancer research. This microenvironment can be modelled in vitro by culturing multicellular tumor spheroids (MCTS). Key challenges when using MCTS in applications such as high-throughput drug screening are overcoming imaging and analytical issues encountered during functional and structural investigations. To address these challenges, we use an ultrasonic standing wave (USW) based MCTS culture platform for parallel formation, staining and imaging of 100 whole MCTS. A protein repellent amphiphilic polymer coating enables flexible production of high quality and unanchored MCTS. This enables high-content multimode analysis based on flow cytometry and in situ optical microscopy. We use HepG2 hepatocellular carcinoma, A498 and ACHN renal carcinoma, and LUTC-2 thyroid carcinoma cell lines to demonstrate (i) the importance of the ultrasound-coating combination, (ii) bright field image based automatic characterization of MTCS, (iii) detailed deep tissue confocal imaging of whole MCTS mounted in a refractive index matching solution, and (iv) single cell functional analysis through flow cytometry of single cell suspensions of disintegrated MTCS. The USW MCTS culture platform is customizable and holds great potential for detailed multimode MCTS analysis in a high-content manner.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:kth:diva-234606 (URN)10.1039/c8lc00537k (DOI)000442265100012 ()30033460 (PubMedID)2-s2.0-85051357097 (Scopus ID)
Funder
Stockholm County CouncilSwedish Cancer SocietySwedish Childhood Cancer FoundationSwedish Research CouncilSwedish Foundation for Strategic Research
Note

QC 20180914

Available from: 2018-09-14 Created: 2018-09-14 Last updated: 2018-09-14Bibliographically approved
Oei, V. Y., Siernicka, M., Graczyk-Jarzynka, A., Hoel, H. J., Yang, W., Palacios, D., . . . Malmberg, K.-J. (2018). Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors. CANCER IMMUNOLOGY RESEARCH, 6(4), 467-480
Open this publication in new window or tab >>Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors
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2018 (English)In: CANCER IMMUNOLOGY RESEARCH, ISSN 2326-6066, Vol. 6, no 4, p. 467-480Article in journal (Refereed) Published
Abstract [en]

Natural killer (NK) cells hold potential as a source of allogeneic cytotoxic effector cells for chimeric antigen receptor (CAR)-mediated therapies. Here, we explored the feasibility of transfecting CAR-encoding mRNA into primary NK cells and investigated how the intrinsic potential of discrete NK-cell subsets affects retargeting efficiency. After screening five second- and third-generation anti-CD19 CAR constructs with different signaling domains and spacer regions, a third-generation CAR with the CH2-domain removed was selected based on its expression and functional profiles. Kinetics experiments revealed that CAR expression was optimal after 3 days of IL15 stimulation prior to transfection, consistently achieving over 80% expression. CAR-engineered NK cells acquired increased degranulation toward CD19(+) targets, and maintained their intrinsic degranulation response toward CD19(-) K562 cells. The response of redirected NK-cell subsets against CD19(+) targets was dependent on their intrinsic thresholds for activation determined through both differentiation and education by killer cell immunoglobulin-like receptors (KIR) and/or CD94/NKG2A binding to self HLA class I and HLA-E, respectively. Redirected primary NK cells were insensitive to inhibition through NKG2A/HLA-E interactions but remained sensitive to inhibition through KIR depending on the amount of HLA class I expressed on target cells. Adaptive NK cells, expressing NKG2C, CD57, and self-HLA-specific KIR(s), displayed superior ability to kill CD19(+), HLA low, or mismatched tumor cells. These findings support the feasibility of primary allogeneic NK cells for CAR engineering and highlight a need to consider NK-cell diversity when optimizing efficacy of cancer immunotherapies based on CAR-expressing NK cells.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-228141 (URN)10.1158/2326-6066.CIR-17-0207 (DOI)000429044000010 ()29459477 (PubMedID)2-s2.0-85048084731 (Scopus ID)
Note

QC 20180518

Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2018-10-16Bibliographically approved
Stikvoort, A., Gaballa, A., Solders, M., Nederlof, I., Önfelt, B., Sundberg, B., . . . Uhlin, M. (2018). Risk Factors for Severe Acute Graft-versus-Host Disease in Donor Graft Composition. Biology of blood and marrow transplantation, 24(3), 467-477
Open this publication in new window or tab >>Risk Factors for Severe Acute Graft-versus-Host Disease in Donor Graft Composition
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2018 (English)In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 24, no 3, p. 467-477Article in journal (Refereed) Published
Abstract [en]

Acute graft-versus-host disease (aGVHD) is 1 of the main major complications of post-hematopoietic stem cell transplantation (HSCT). Identifying patients at risk of severe aGVHD may lead to earlier intervention and treatment, resulting in increased survival and a better quality of life. We aimed to identify biomarkers in donor grafts and patient plasma around the time of transplantation that might be predictive of aGVHD development. We build on our previously published methods by using multiplex assays and multicolor flow cytometry. We identified 5 easily assessable cellular markers in donor grafts that combined could potentially be used to calculate risk for severe aGVHD development. Most noteworthy are the T cell subsets expressing IL-7 receptor-a (CD127) and PD-1. Additionally, we identified a potential role for elevated tumor necrosis factor-a levels in both graft and patient before HSCT in development of aGVHD. 

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2018
Keywords
Stem cell transplantation, GVHD, T cells, Donor grafts, Risk factors
National Category
Basic Medicine
Identifiers
urn:nbn:se:kth:diva-225738 (URN)10.1016/j.bbmt.2017.11.026 (DOI)000427663000008 ()29197674 (PubMedID)
Funder
Swedish Research CouncilStockholm County CouncilSwedish Foundation for Strategic Research
Note

QC 20180410

Available from: 2018-04-10 Created: 2018-04-10 Last updated: 2018-04-10Bibliographically approved
Brandt, L., Pfefferle, A., Goodridge, J., Malmberg, K.-J. & Önfelt, B. (2017). Cytotoxicity and killing kinetics of KIR educated NK cells. Paper presented at 44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN. Scandinavian Journal of Immunology, 86(4), 301-301
Open this publication in new window or tab >>Cytotoxicity and killing kinetics of KIR educated NK cells
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2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 301-301Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
WILEY, 2017
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-215793 (URN)000411865200127 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20171018

Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2017-10-18Bibliographically approved
Fogelqvist, E., Kördel, M., Carannante, V., Önfelt, B. & Hertz, H. (2017). Laboratory cryo x-ray microscopy for 3D cell imaging. Scientific Reports, 7, Article ID 13433.
Open this publication in new window or tab >>Laboratory cryo x-ray microscopy for 3D cell imaging
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 13433Article in journal (Refereed) Published
Abstract [en]

Water-window x-ray microscopy allows two-and three-dimensional (2D and 3D) imaging of intact unstained cells in their cryofixed near-native state with unique contrast and high resolution. Present operational biological water-window microscopes are based at synchrotron facilities, which limits their accessibility and integration with complementary methods. Laboratory-source microscopes have had difficulty addressing relevant biological tasks with proper resolution and contrast due to long exposure times and limited up-time. Here we report on laboratory cryo x-ray microscopy with the exposure time, contrast, and reliability to allow for routine high-spatial resolution 3D imaging of intact cells and cell-cell interactions. Stabilization of the laser-plasma source combined with new optics and sample preparation provide high-resolution cell imaging, both in 2D with ten-second exposures and in 3D with twenty-minute tomography. Examples include monitoring of the distribution of carbon-dense vesicles in starving HEK293T cells and imaging the interaction between natural killer cells and target cells.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Physical Sciences
Identifiers
urn:nbn:se:kth:diva-217434 (URN)10.1038/s41598-017-13538-2 (DOI)000413188400014 ()29044158 (PubMedID)2-s2.0-85031924153 (Scopus ID)
Note

QC 20171117

Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2017-11-17Bibliographically approved
Verron, Q., Guldevall, K., Brandt, L., Olofsson, P. E., Frisk, T. & Önfelt, B. (2017). Microchip screening for single cell assessment and isolation of serial killing NK cells. Paper presented at 44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN. Scandinavian Journal of Immunology, 86(4), 347-347
Open this publication in new window or tab >>Microchip screening for single cell assessment and isolation of serial killing NK cells
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2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 347-347Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
WILEY, 2017
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-215798 (URN)000411865200230 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Note

QC 20171018

Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2017-10-18Bibliographically approved
Carannante, V., Olofsson, K., Van Oojen, H., Edwards, S., Brismar, H., Lundqvist, A., . . . Önfelt, B. (2017). Novel platform for studying infiltration, migration and cytotoxicity of human Natural Killer cells in solid tumors. Paper presented at 44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN. Scandinavian Journal of Immunology, 86(4), 315-315
Open this publication in new window or tab >>Novel platform for studying infiltration, migration and cytotoxicity of human Natural Killer cells in solid tumors
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2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 315-315Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
WILEY, 2017
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-215794 (URN)000411865200163 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Note

QC 20171018

Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2017-10-18Bibliographically approved
Meinke, S., Brandt, L., Sandgren, P., Önfelt, B. & Hoglund, P. (2017). Platelets become NK cell targets in the presence of anti-platelet antibodies. Paper presented at 44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN. Scandinavian Journal of Immunology, 86(4), 257-258
Open this publication in new window or tab >>Platelets become NK cell targets in the presence of anti-platelet antibodies
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2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 257-258Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
WILEY, 2017
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-215788 (URN)000411865200028 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Note

QC 20171018

Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2017-10-18Bibliographically approved
Guldevall, K., Brandt, L., Forslund, E., Olofsson, K., Frisk, T. W., Olofsson, P. E., . . . Önfelt, B. (2016). Microchip screening Platform for single cell assessment of NK cell cytotoxicity. Frontiers in Immunology, 7, Article ID 119.
Open this publication in new window or tab >>Microchip screening Platform for single cell assessment of NK cell cytotoxicity
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2016 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, article id 119Article in journal (Refereed) Published
Abstract [en]

Here, we report a screening platform for assessment of the cytotoxic potential of individual natural killer (NK) cells within larger populations. Human primary NK cells were distributed across a silicon-glass microchip containing 32,400 individual microwells loaded with target cells. Through fluorescence screening and automated image analysis, the numbers of NK and live or dead target cells in each well could be assessed at different time points after initial mixing. Cytotoxicity was also studied by time-lapse live-cell imaging in microwells quantifying the killing potential of individual NK cells. Although most resting NK cells (approximate to 75%) were non-cytotoxic against the leukemia cell line K562, some NK cells were able to kill several (>= 3) target cells within the 12-h long experiment. In addition, the screening approach was adapted to increase the chance to find and evaluate serial killing NK cells. Even if the cytotoxic potential varied between donors, it was evident that a small fraction of highly cytotoxic NK cells were responsible for a substantial portion of the killing. We demonstrate multiple assays where our platform can be used to enumerate and characterize cytotoxic cells, such as NK or T cells. This approach could find use in clinical applications, e.g., in the selection of donors for stem cell transplantation or generation of highly specific and cytotoxic cells for adoptive immunotherapy.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2016
Keywords
NK cells, cytotoxicity, single cell analysis, microchip, screening, microscopy, fluorescence, immune synapse
National Category
Immunology
Identifiers
urn:nbn:se:kth:diva-185604 (URN)10.3389/fimmu.2016.00119 (DOI)000373340600001 ()2-s2.0-84966702164 (Scopus ID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research Swedish Childhood Cancer FoundationSwedish Cancer Society
Note

QC 20160428

Available from: 2016-04-28 Created: 2016-04-25 Last updated: 2017-11-30Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5178-7593

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