| 1. |
- Cedervall, Jessica, et al.
(författare)
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Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.
- 2017
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Ingår i: Oncoimmunology. - : Taylor & Francis. - 2162-4011 .- 2162-402X. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.
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| 2. |
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| 3. |
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| 4. |
- Femel, Julia, 1986-, et al.
(författare)
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Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer.
- 2014
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 5:23, s. 12418-12427
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic vaccination targeting self-molecules is an attractive alternative to monoclonal antibody-based therapies for cancer and various inflammatory diseases. However, development of cancer vaccines targeting self-molecules has proven difficult. One complicating factor is that tumor cells have developed strategies to escape recognition by the immune system. Antigens specifically expressed by the tumor vasculature can therefore provide alternative targets. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin are expressed during vasculogenesis in the embryo, but essentially undetectable under normal conditions in the adult. However, these domains are re-expressed during tumor angiogenesis and matrix remodeling, which renders them highly interesting for targeted cancer therapies. Using the MMTV-PyMT transgenic model of metastatic mammary carcinoma, we show that tumor burden can be significantly decreased by immunization against ED-A in a therapeutic setting. Furthermore, we found that in mice carrying anti-ED-A antibodies the number of metastases was reduced. ED-A immunization increased infiltration of macrophages and compromised tumor blood vessel function. These findings implicate an attack of the tumor vasculature by the immune system, through a polyclonal antibody response. We conclude that tumor vascular antigens are promising candidates for development of therapeutic vaccines targeting growth of primary tumors as well as disseminated disease.
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| 5. |
- Femel, Julia, 1986-, et al.
(författare)
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Vaccination against galectin-1 promotes cytotoxic T-cell infiltration in melanoma and reduces tumor burden
- 2022
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Ingår i: Cancer Immunology and Immunotherapy. - : Springer Nature. - 0340-7004 .- 1432-0851. ; 71:8, s. 2029-2040
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-1 (Gal1) is a glycan-binding protein that promotes tumor progression by several distinct mechanisms. Through direct binding to vascular endothelial growth factor (VEGF)-receptor 2, Gal1 is able to induce VEGF-like signaling, which contributes to tumor angiogenesis. Furthermore, several studies have demonstrated an immunosuppressive function of Gal1 through effects on both effector and regulatory T cells. Elevated Gal1 expression and secretion have been shown in many tumor types, and high Gal1 serum levels have been connected to poor prognosis in cancer patients. These findings suggest that therapeutic strategies directed against Gal1 would enable simultaneous targeting of angiogenesis, immune evasion and metastasis. In the current study, we have analyzed the potential of Gal1 as a cancer vaccine target. We show that it is possible to generate high anti-Gal1 antibody levels in mice immunized with a recombinant vaccine protein consisting of bacterial sequences fused to Gal1. Growth of Gal1 expressing melanomas was significantly impaired in the immunized mice compared to the control group. This was associated with improved perfusion of the tumor vasculature, as well as increased infiltration of macrophages and cytotoxic T cells (CTLs). The level of granzyme B, mainly originating from CTLs in our model, was significantly elevated in Gal1 vaccinated mice and correlated with a decrease in tumor burden. We conclude that vaccination against Gal1 is a promising pro-immunogenic approach for cancer therapy that could potentially enhance the effect of other immunotherapeutic strategies due to its ability to promote CTL influx in tumors.
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| 6. |
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| 7. |
- Saupe, Falk, et al.
(författare)
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Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously
- 2017
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Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 31:3, s. 1204-1214
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Tidskriftsartikel (refereegranskat)abstract
- With the aim to improve the efficacy of therapeutic vaccines that target self-antigens, we have developed a novel fusion protein vaccine on the basis of the C-terminal multimerizing end of the variable lymphocyte receptor B (VLRB), the Ig equivalent in jawless fishes. Recombinant vaccines were produced in Escherichia coli by fusing the VLRB sequence to 4 different cancer-associated target molecules. The anti-self-immune response generated in mice that were vaccinated with VLRB vaccines was compared with the response in mice that received vaccines that contained bacterial thioredoxin (TRX), previously identified as an efficient carrier. The anti-self-Abswere analyzed with respect to titers, binding properties, and duration of response. VLRB-vaccinatedmice displayed a 2-to 10-fold increase in anti-self-Ab titers and a substantial decrease in Abs against the foreign part of the fusion protein compared with the response in TRX-vaccinated mice (P < 0.01). VLRB-generated Ab response had duration similar to the corresponding TRX-generatedAbs, but displayed a higher diversity in binding characteristics. Of importance, VLRB vaccines could sustain an immune response against several targets simultaneously. VLRB vaccines fulfill several key criteria for an efficient therapeutic vaccine that targets self-antigens as a result of its small size, its multimerizing capacity, and nonexposed foreign sequences in the fusion protein.- Saupe, F., Reichel, M., Huijbers, E. J. M., Femel, J., Markgren, P.- O., Andersson, C. E., Deindl, S., Danielson, U. H., Hellman, L. T., Olsson, A.- K. Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously.
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| 8. |
- Saupe, Falk, et al.
(författare)
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Vaccines targeting self-antigens : mechanisms and efficacy-determining parameters
- 2015
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 29:8, s. 3253-3262
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Tidskriftsartikel (refereegranskat)abstract
- We recently showed that it is possible to compromise tumor vessel function and, as a consequence, suppress growth of aggressive preclinical tumors by immunizing against the tumor vascular markers extra domain-A (ED-A) or -B (ED-B) of fibronectin, using a fusion protein consisting of the ED-A or ED-B peptide fused to bacterial thioredoxin. To address the mechanism behind fusion protein-induced immunization and the specific contribution of the different vaccine constituents to elicit an anti-self-antibody response, we immunized mice with modified or unmodified self-antigens, combined with different adjuvant components, and analyzed antibody responses by ELISA in sera. Several essential requirements to circumvent tolerance were identified: (1) a potent pattern recognition receptor agonist like an oligonucleotide containing unmethylated cytosine and guanine dinucleotides (CpG); (2) a depot adjuvant to keep the CpG at the site of injection; and (3) the presence of foreign sequences in the vaccine protein. Lack of either of these factors abolished the anti-self-response (P = 0.008). In mice genetically deficient for type I IFN signaling, there was a 60% reduction in the anti-self-response compared with wildtype (P = 0.011), demonstrating a key role of this pathway in CpG-induced circumvention of self-tolerance. Identification of these mechanistic requirements to generate a potent anti-self-immune response should significantly aid the design of efficient, specific, and safe therapeutic cancer vaccines.
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| 9. |
- Spenle, Caroline, et al.
(författare)
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Tenascin-C : Exploitation and collateral damage in cancer management
- 2015
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Ingår i: CELL ADHESION & MIGRATION. - : Informa UK Limited. - 1933-6918 .- 1933-6926. ; 9:1-2, s. 141-153
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Forskningsöversikt (refereegranskat)abstract
- Despite an increasing knowledge about the causes of cancer, this disease is difficult to cure and still causes far too high a death rate. Based on advances in our understanding of disease pathogenesis, novel treatment concepts, including targeting the tumor microenvironment, have been developed and are being combined with established treatment regimens such as surgical removal and radiotherapy. Yet it is obvious that we need additional strategies to prevent tumor relapse and metastasis. Given its exceptional high expression in most cancers with low abundance in normal tissues, tenascin-C appears an ideal candidate for tumor treatment. Here, we will summarize the current applications of targeting tenascin-C as a treatment for different tumors, and highlight the potential of this therapeutic approach.
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| 10. |
- Zhang, Yanyu, et al.
(författare)
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TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells
- 2019
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Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 33:7, s. 7822-7832
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Tidskriftsartikel (refereegranskat)abstract
- Platelets can promote several stages of the metastatic process and thus contribute to malignant progression. As an example, platelets promote invasive properties of tumor cells by induction of epithelial to mesenchymal transition (EMT). In this study, we show that tumor necrosis factor receptor-associated factor (TRAF) family member-associated NF-kappa B activator (TANK)-binding kinase 1 (TBK1) is a previously unknown mediator of platelet-induced EMT in mammary carcinoma cells. Coculture of 2 mammary carcinoma cell lines, Ep5 from mice and MCF10A(MII) from humans, with isolated platelets induced morphologic as well as molecular changes characteristic of EMT, which was paralleled with activation of TBK1. TBK1 depletion using small interfering RNA impaired platelet-induced EMT in both Ep5 and MCF10A(MII) cells. Furthermore, platelet-induced activation of the NF-kappa B subunit p65 was suppressed after TBK1 knockdown, demonstrating that TBK1 mediates platelet-induced NF-kappa B signaling and EMT. Using an in vivo metastasis assay, we found that depletion of TBK1 from mammary carcinoma cells during in vitro preconditioning with platelets subsequently suppressed the formation of lung metastases in mice. Altogether, these results suggest that TBK1 contributes to tumor invasiveness and may be a driver of metastatic spread in breast cancer.-Zhang, Y., Unnithan, R. V. M., Hamidi, A., Caja, L., Saupe, F., Moustakas, A., Cedervall, J., Olsson, A.-K. TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells.
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