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Publications (10 of 77) Show all publications
Fotaki, G., Jin, C., Kerzeli, I. K., Ramachandran, M., Martikainen, M.-M., Karlsson-Parra, A., . . . Essand, M. (2018). Cancer vaccine based on a combination of an infection-enhanced adenoviral vector and pro-inflammatory allogeneic DCs leads to sustained antigen-specific immune responses in three melanoma models. Oncoimmunology, 7(3), Article ID e1397250.
Open this publication in new window or tab >>Cancer vaccine based on a combination of an infection-enhanced adenoviral vector and pro-inflammatory allogeneic DCs leads to sustained antigen-specific immune responses in three melanoma models
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2018 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 7, no 3, article id e1397250Article in journal (Refereed) Published
Abstract [en]

Autologous patient-derived dendritic cells (DCs) modified ex vivo to present tumor-associated antigens (TAAs) are frequently used as cancer vaccines. However, apart from the stringent logistics in producing DCs on a patient basis, accumulating evidence indicate that ex vivo engineered DCs are poor in migration and in fact do not directly present TAA epitopes to naïve T cells in vivo. Instead, it is proposed that bystander host DCs take up material from vaccine-DCs, migrate and subsequently initiate antitumor T-cell responses. We used mouse models to examine the possibility of using pro-inflammatory allogeneic DCs (alloDCs) to activate host DCs and enable them to promote antigen-specific T-cell immunity. We found that alloDCs were able to initiate host DC activation and migration to draining lymph node leading to T-cell activation. The pro-inflammatory milieu created by alloDCs also led to recruitment of NK cells and neutrophils at the site of injection. Vaccination with alloDCs combined with Ad5M(gp100), an infection-enhanced adenovirus encoding the human melanoma-associated antigen gp100 resulted in generation of CD8+ T cells with a T-cell receptor (TCR) specific for the gp10025-33 epitope (gp100-TCR+). Ad5M(gp100)-alloDC vaccination in combination with transfer of gp100-specific pmel-1 T cells resulted in prolonged survival of B16-F10 melanoma-bearing mice and altered the composition of the tumor microenvironment (TME). We hereby propose that alloDCs together with TAA- or neoepitope-encoding Ad5M can become an “off-the-shelf” cancer vaccine, which can reverse the TME-induced immunosuppression and induce host cellular anti-tumor immune responses in patients without the need of a time-consuming preparation step of autologous DCs.

Keywords
adjuvants, Allogeneic dendritic cells, cell-based immunotherapy, tumor microenvironment, tumor-associated antigen
National Category
Cancer and Oncology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-346362 (URN)10.1080/2162402X.2017.1397250 (DOI)000423567000013 ()29399398 (PubMedID)
Funder
Swedish Cancer Society, CAN 2013/373; CAN 2016/318Swedish Childhood Cancer Foundation, PR2015-0049Swedish Research Council, 2015-03688
Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2018-03-16Bibliographically approved
Roche, F. P., Pietilä, I., Kaito, H., Sjöström, E. O., Sobotzki, N., Noguer, O., . . . Claesson-Welsh, L. (2018). Leukocyte differentiation by histidine-rich glycoprotein/stanniocalcin-2 complex regulates murine glioma growth through modulation of anti-tumor immunity. Molecular Cancer Therapeutics, 17(9), 1961-1972
Open this publication in new window or tab >>Leukocyte differentiation by histidine-rich glycoprotein/stanniocalcin-2 complex regulates murine glioma growth through modulation of anti-tumor immunity
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2018 (English)In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 17, no 9, p. 1961-1972Article in journal (Refereed) Published
Abstract [en]

The plasma-protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and anti-tumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction-decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and co-localization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG treated gliomas displayed decreased numbers of Interleukin-35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control anti-tumor immunity.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-356836 (URN)10.1158/1535-7163.MCT-18-0097 (DOI)29945872 (PubMedID)
Funder
Swedish Cancer Society, 16 0585Swedish Cancer Society, 16 0520Swedish Research Council, 2015-02375_3Swedish Research Council, 2016-01085
Note

I. Pietilä and H. Kaito contributed equally to this article.

Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-09-05Bibliographically approved
Younis, S., Kamel, W., Falkeborn, T., Wang, H., Yu, D., Daniels, R., . . . Andersson, L. (2018). Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth. Proceedings of the National Academy of Sciences of the United States of America, 115(16), E3808-E3816
Open this publication in new window or tab >>Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 16, p. E3808-E3816Article in journal (Refereed) Published
Abstract [en]

The zinc finger CCCH-type containing 11A (ZC3H11A) gene encodes a well-conserved zinc finger protein that may function in mRNA export as it has been shown to associate with the transcription export (TREX) complex in proteomic screens. Here, we report that ZC3H11A is a stress-induced nuclear protein with RNA-binding capacity that localizes to nuclear splicing speckles. During an adenovirus infection, the ZC3H11A protein and splicing factor SRSF2 relocalize to nuclear regions where viral DNA replication and transcription take place. Knockout (KO) of ZC3H11A in HeLa cells demonstrated that several nuclear-replicating viruses are dependent on ZC3H11A for efficient growth (HIV, influenza virus, herpes simplex virus, and adenovirus), whereas cytoplasmic replicating viruses are not (vaccinia virus and Semliki Forest virus). High-throughput sequencing of ZC3H11A-cross-linked RNA showed that ZC3H11A binds to short purine-rich ribonucleotide stretches in cellular and adenoviral transcripts. We show that the RNA-binding property of ZC3H11A is crucial for its function and localization. In ZC3H11A KO cells, the adenovirus fiber mRNA accumulates in the cell nucleus. Our results suggest that ZC3H11A is important for maintaining nuclear export of mRNAs during stress and that several nuclear-replicating viruses take advantage of this mechanism to facilitate their replication.

Keywords
ZC3H11A, mRNA export, stress response, virus infection
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-354118 (URN)10.1073/pnas.1722333115 (DOI)000430191900026 ()29610341 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-06-19Bibliographically approved
Fotaki, G., Jin, C., Ramachandran, M., Kerzeli, I. K., Karlsson-Parra, A., Yu, D. & Essand, M. (2018). Pro-inflammatory allogeneic DCs promote activation of bystander immune cells and thereby license antigen-specific T-cell responses. Oncoimmunology, 7(3), Article ID e1395126.
Open this publication in new window or tab >>Pro-inflammatory allogeneic DCs promote activation of bystander immune cells and thereby license antigen-specific T-cell responses
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2018 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 7, no 3, article id e1395126Article in journal (Refereed) Published
Abstract [en]

Accumulating evidence support an important role for endogenous bystander dendritic cells (DCs) in the efficiency of autologous patient-derived DC-vaccines, as bystander DCs take up material from vaccine-DCs, migrate to draining lymph node and initiate antitumor T-cell responses. We examined the possibility of using allogeneic DCs as vaccine-DCs to activate bystander immune cells and promote antigen-specific T-cell responses. We demonstrate that human DCs matured with polyI:C, R848 and IFN-γ (denoted COMBIG) in combination with an infection-enhanced adenovirus vector (denoted Ad5M) exhibit a pro-inflammatory state. COMBIG/Ad5M-matured allogeneic DCs (alloDCs) efficiently activated T-cells and NK-cells in allogeneic co-culture experiments. The secretion of immunostimulatory factors during the co-culture promoted the maturation of bystander-DCs, which efficiently cross-presented a model-antigen to activate antigen-specific CD8+ T-cells in vitro. We propose that alloDCs, in combination with Ad5M as loading vehicle, may be a cost-effective and logistically simplified DC vaccination strategy to induce anti-tumor immune responses in cancer patients.

Keywords
Allogeneic dendritic cells, cell-based immunotherapy, innate immune cells, cell activation
National Category
Immunology in the medical area Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-346363 (URN)10.1080/2162402X.2017.1395126 (DOI)000423567000006 ()
Funder
Swedish Cancer Society, CAN 2013/373; CAN 2016/318Swedish Childhood Cancer Foundation, PR2015-0049Swedish Research Council, 2015-03688
Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2018-03-16Bibliographically approved
Ma, J., Ramachandran, M., Jin, C., Essand, M. & Yu, D. (2017). Adenovirus, Semliki Forest virus and vaccinia virus-induced immunogenic cell death augments oncolytic virus immunotherapy. 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), 341-341
Open this publication in new window or tab >>Adenovirus, Semliki Forest virus and vaccinia virus-induced immunogenic cell death augments oncolytic virus immunotherapy
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2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 341-341Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-346971 (URN)000411865200218 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-03-27Bibliographically approved
Essand, M., Ma, J., Jin, C., Ramachandran, M. & Yu, D. (2017). CAR T-Cells with Induced Secretion of Helicobacter Pylori Neutrophil-Activating Protein (HP-NAP) Yields Improved Anti-Tumor Activity and Reduced Immunosuppression. Paper presented at 20th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 10-13, 2017, Washington, DC. Molecular Therapy, 25(5 S1), 288-288
Open this publication in new window or tab >>CAR T-Cells with Induced Secretion of Helicobacter Pylori Neutrophil-Activating Protein (HP-NAP) Yields Improved Anti-Tumor Activity and Reduced Immunosuppression
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2017 (English)In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 25, no 5 S1, p. 288-288Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-331372 (URN)000401083600621 ()
Conference
20th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 10-13, 2017, Washington, DC
Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2017-10-18Bibliographically approved
Lövgren, T., Wenthe, J., Karlsson, S. C., Gammelgård, G., Essand, M., Savoldo, B., . . . Loskog, A. (2017). Immunological biomarkers correlate to survival in CAR19-treated patients. 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), 337-337
Open this publication in new window or tab >>Immunological biomarkers correlate to survival in CAR19-treated patients
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2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 337-337Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-346970 (URN)000411865200208 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-03-27Bibliographically approved
Martikainen, M., Ruotsalainen, J., Tuomela, J., Harkonen, P., Essand, M., Heikkila, J. & Hinkkanen, A. (2017). Oncolytic alphavirus SFV-VA7 efficiently eradicates subcutaneous and orthotopic human prostate tumours in mice. British Journal of Cancer, 117(1), 51-55
Open this publication in new window or tab >>Oncolytic alphavirus SFV-VA7 efficiently eradicates subcutaneous and orthotopic human prostate tumours in mice
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2017 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 117, no 1, p. 51-55Article in journal (Refereed) Published
Abstract [en]

Background: Despite recent therapeutic and diagnostic advances, prostate cancer remains the second leading cause of cancer-related deaths among men in the Western world. Oncolytic viruses that replicate selectively in tumour cells represent a novel treatment candidate for these malignancies.

Methods: We analysed infectivity of avirulent Semliki Firest virus SFV-VA7 in human prostate cancer cell lines VCaP, LNCaP and 22Rv1 and in nonmalignant prostate epithelial cell line RWPE-1. Therapeutic potency of SFV-VA7 was evaluated in subcutaneous and orthotopic mouse LNCaP xenograft models.

Results: SFV-VA7 infected and killed the tested human prostate cancer cell lines irrespective of their hormone response status, while the nonmalignant prostate epithelial cell line RWPE-1 proved highly virus resistant. Notably, a single peritoneal dose of SFV-VA7 was sufficient to eradicate all subcutaneous and orthotopic LNCaP tumours.

Conclusions: Our results indicate that SFV-VA7 is a novel, promising therapeutic virus against prostate cancer warranting further testing in early clinical trials.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
Keywords
oncolytic virotherapy, alphavirus, semliki forest virus, prostate cancer, orthotopic tumour model, xenograft tumour model
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-329638 (URN)10.1038/bjc.2017.151 (DOI)000404111300007 ()28557974 (PubMedID)
Available from: 2017-09-26 Created: 2017-09-26 Last updated: 2017-09-26Bibliographically approved
Pan, G., Ameur, A., Enroth, S., Bysani, M., Nord, H., Cavalli, M., . . . Wadelius, C. (2017). PATZ1 down-regulates FADS1 by binding to rs174557 and is opposed by SP1/SREBP1c. Nucleic Acids Research, 45(5), 2408-2422
Open this publication in new window or tab >>PATZ1 down-regulates FADS1 by binding to rs174557 and is opposed by SP1/SREBP1c
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2017 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 5, p. 2408-2422Article in journal (Refereed) Published
Abstract [en]

The FADS1 and FADS2 genes in the FADS cluster encode the rate-limiting enzymes in the synthesis of long-chain polyunsaturated fatty acids (LC-PUFAs). Genetic variation in this region has been associated with a large number of diseases and traits many of them correlated to differences in metabolism of PUFAs. However, the causative variants leading to these associations have not been identified. Here we find that the multiallelic rs174557 located in an AluYe5 element in intron 1 of FADS1 is functional and lies within a PATZ1 binding site. The derived allele of rs174557, which is the common variant in most populations, diminishes binding of PATZ1, a transcription factor conferring allele-specific downregulation of FADS1 The PATZ1 binding site overlaps with a SP1 site. The competitive binding between the suppressive PATZ1 and the activating complex of SP1 and SREBP1c determines the enhancer activity of this region, which regulates expression of FADS1.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-317999 (URN)10.1093/nar/gkw1186 (DOI)000397286600024 ()27932482 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research Council, 521-2010-3505 6212011-6052 521-2012-2884Swedish Diabetes AssociationSwedish Cancer Society, 15 0878
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2017-04-18Bibliographically approved
Ramachandran, M., Yu, D., Dyczynski, M., Baskaran, S., Zhang, L., Lulla, A., . . . Essand, M. (2017). Safe and effective treatment of experimental neuroblastoma and glioblastoma using systemically administered triple microRNA-detargeted oncolytic Semliki Forest virus. Clinical Cancer Research, 23(6), 1519-1530
Open this publication in new window or tab >>Safe and effective treatment of experimental neuroblastoma and glioblastoma using systemically administered triple microRNA-detargeted oncolytic Semliki Forest virus
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2017 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 6, p. 1519-1530Article in journal (Refereed) Published
Abstract [en]

PURPOSE:

Glioblastoma multiforme (GBM) and high-risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic strategy for these malignancies. Here we evaluate the oncolytic potential of the neurovirulent and partly interferon (IFN)-β-resistant Semliki Forest virus (SFV)-4 in GBMs and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal CNS cells through insertion of microRNA target sequences for miR124, miR125, miR134 Experimental Design:Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and GBM cell lines and in patient-derived human glioblastoma cell cultures (HGCC). In vivo neurovirulence and therapeutic efficacy was evaluated in two syngeneic orthotopic glioma models (CT-2A, GL261) and syngeneic subcutaneous neuroblastoma model (NXS2). The role of IFN-β in inhibiting therapeutic efficacy was investigated.

RESULTS:

The introduction of microRNA target sequences reduced neurovirulence of SFV4 in terms of attenuated replication in mouse CNS cells and ability to cause encephalitis when administered intravenously. A single intravenous injection of SFV4miRT prolonged survival and cured 4 of 8 mice (50%) with NXS2 and 3 of 11 mice (27%) with CT-2A, but not for GL261 tumor bearing mice. In vivo therapeutic efficacy in different tumor models inversely correlated to secretion of IFN-β by respective cells upon SFV4 infection in vitro Similarly, killing efficacy of HGCC lines inversely correlated to IFN-β response and interferon-α⁄β receptor (IFNAR)-1 expression.

CONCLUSIONS:

SFV4miRT has reduced neurovirulence, while retaining its oncolytic potential. SFV4miRT is an excellent candidate for treatment of GBMs and neuroblastomas with low IFN-β secretion.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2017
Keywords
Semliki Forest virus, Glioblastoma, Neuroblastoma, Oncolytic virus immunotherapy, Type-I antiviral response
National Category
Other Basic Medicine
Research subject
Oncology; Biology with specialization in Molecular Biotechnology
Identifiers
urn:nbn:se:uu:diva-303633 (URN)10.1158/1078-0432.CCR-16-0925 (DOI)000397344800018 ()27637889 (PubMedID)
Funder
Swedish Research Council, K2013-22191-01-3Swedish Cancer Society, CAN2013/373Swedish Childhood Cancer Foundation, PROJ12/082
Available from: 2016-09-21 Created: 2016-09-21 Last updated: 2018-01-10Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9725-0422

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