| 1. |
- Bogefors, Jesper, et al.
(författare)
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LEAP-2, LL-37 and RNase7 in tonsillar tissue: downregulated expression in seasonal allergic rhinitis.
- 2014
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Ingår i: Pathogens and Disease. - 2049-632X. ; 72:1, s. 55-60
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Tidskriftsartikel (refereegranskat)abstract
- In the upper airway, the production of antimicrobial peptides (AMPs) protects against bacteria, viruses and fungi. Previous investigations have revealed downregulated expression of AMPs in different manifestations of allergic disease. In this study, we examined the expression of LL-37, RNase7 and LEAP-2 in tonsillar tissue and studied a possible relation to seasonal allergic rhinitis (SAR).
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| 2. |
- Gunnarsdottir, Frida Björk, et al.
(författare)
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Breast cancer associated CD169(+) macrophages possess broad immunosuppressive functions but enhance antibody secretion by activated B cells
- 2023
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Ingår i: Frontiers in Immunology. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- CD169(+) resident macrophages in lymph nodes of breast cancer patients are for unknown reasons associated with a beneficial prognosis. This contrasts CD169(+) macrophages present in primary breast tumors (CD169(+) TAMs), that correlate with a worse prognosis. We recently showed that these CD169(+) TAMs were associated with tertiary lymphoid structures (TLSs) and T-regs in breast cancer. Here, we show that CD169(+) TAMs can be monocyte-derived and express a unique mediator profile characterized by type I IFNs, CXCL10, PGE(2) and inhibitory co-receptor expression pattern. The CD169(+) monocyte-derived macrophages (CD169(+) Mo-M) possessed an immunosuppressive function in vitro inhibiting NK, T and B cell proliferation, but enhanced antibody and IL6 secretion in activated B cells. Our findings indicate that CD169(+) Mo-M in the primary breast tumor microenvironment are linked to both immunosuppression and TLS functions, with implications for future targeted Mo-M therapy.
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| 3. |
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| 4. |
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| 5. |
- Mehmeti-Ajradini, Meliha, et al.
(författare)
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Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer
- 2020
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Ingår i: Life Science Alliance. - 2575-1077. ; 3:11
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Tidskriftsartikel (refereegranskat)abstract
- Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients cotransplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.
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| 6. |
- Mehmeti-Ajradini, Meliha, et al.
(författare)
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Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer
- 2020
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Ingår i: Life Science Alliance. - : LIFE SCIENCE ALLIANCE LLC. - 2575-1077. ; 3:11
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Tidskriftsartikel (refereegranskat)abstract
- Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients co-transplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.
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| 7. |
- Mehmeti, Meliha, et al.
(författare)
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Wnt5a is a TLR2/4-ligand that induces tolerance in human myeloid cells
- 2019
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Innate immune responses are rapid, dynamic and highly regulated to avoid overt reactions. This regulation is executed by innate immune tolerance mechanisms that remain obscure. Wnt5a is a signalling protein mainly involved in developmental processes and cancer. The effect of Wnt5a on inflammatory myeloid cells is controversial. Here, we combine primary cell cultures, in vitro binding studies, mass spectrometry and Drosophila protein modelling to show that Wnt5a is a direct ligand of toll-like receptor (TLR) 2 and 4. The binding promotes a MyD88-non-canonical nuclear factor of kappa B (NFκB) and AP-1 signalling cascade, with contradictory profiles in mouse (pro-inflammatory) and human (anti-inflammatory) myeloid immune cells. These data reveal that the true nature of Wnt5a in inflammatory cells, is to regulate TLR signals, and in human myeloid cells it acts as an endogenous, tolerance-associated molecular pattern (TAMP), inducing IL-10 and innate immune tolerance.
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| 8. |
- Millrud, Camilla Rydberg, et al.
(författare)
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Docetaxel promotes the generation of anti-tumorigenic human macrophages
- 2018
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 362:2, s. 525-531
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Tidskriftsartikel (refereegranskat)abstract
- The taxanes Docetaxel and Paclitaxel are two of the standard chemotherapies for patients with metastatic breast cancer. The functional effect of Docetaxel and Paclitaxel on human innate immune cells of the myeloid lineage is not well established, nor is the effects these agents have on differentiation of monocytes into macrophages and dendritic cells. Therefore, the aim with this project was to determine the effects of Docetaxel and Paclitaxel on primary human monocyte differentiation, activation and function. For this purpose, primary human monocytes were isolated from healthy donors and cultured with or without Docetaxel and Paclitaxel. We found that Docetaxel promoted the differentiation of primary human monocytes into pro-inflammatory macrophages with an M1 phenotype and an ability to present antigens to T cells. Monocytes treated with Docetaxel also displayed an elevated secretion of IL-8 and IL-1β, but did not promote generation of monocytic myeloid-derived suppressor cells. In conclusion, Docetaxel appears to have an immune stimulatory effect that would be beneficial for an anti-tumorigenic type of immune response, whereas Paclitaxel seems to have less effect on myeloid cells.
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| 9. |
- Millrud, Camilla Rydberg, et al.
(författare)
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Nod-like receptors in head and neck squamous cell carcinoma
- 2013
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 133:12, s. 1333-1344
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Tidskriftsartikel (refereegranskat)abstract
- Conclusion: The capability of Nod1 to recognize bacteria along with its altered expression and ability to cause an immunological response in head and neck cancer suggest a novel pathway for bacteria to interfere with ongoing cancer inflammation. Objective: Nucleotide oligomerization domain (Nod)-like receptors (NLRs) comprise a recently discovered family of pattern-recognition receptors. In addition to their protective function against infections, accumulating evidence suggests a role for these receptors in various diseases, including cancer. The present study was designed to explore the presence of NLRs in head and neck squamous cell carcinoma, and to determine if these cells have the ability to respond immunologically to ligand stimulation. Methods: The pharyngeal squamous cell carcinoma cell lines Detroit-562 and FaDu were used as a model for head and neck cancer, and compared to healthy primary human nasal epithelial cells. Analyses were performed using immuno-histochemistry, real-time RT-PCR, Luminex Multiplex Immunoassay, ELISA, and flow cytometry. Results: The expression profile of NLRs in head and neck cancer cells differed from that seen in healthy epithelial cells. Further, Nod1 stimulation induced an immunological response in tumor cells that differed from the response in normal epithelial cells, especially regarding the expression of beta-defensin 2, granulocyte monocyte colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), intercellular adhesion molecule-1 (ICAM-1), and cell survival.
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| 10. |
- Millrud, Camilla Rydberg, et al.
(författare)
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On the origin of myeloid-derived suppressor cells
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:2, s. 3649-3665
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Forskningsöversikt (refereegranskat)abstract
- Myeloid-derived suppressor cells (MDSCs) have a strong immunosuppressive character that allows them to regulate immune responses and hinder overt inflammatory responses. In cancer, this leads to tumor immune evasion and disease progression. MDSCs come in at least two forms: monocytic (Mo-MDSCs) and granulocytic (G-MDSCs). The classical definition of MDSCs as immature myeloid cells blocked from differentiating has been challenged by recent studies suggesting that Mo-MDSCs and G-MDSCs may represent monocytes and granulocytes that have acquired immunosuppressive properties. The molecular mechanism behind their generation and their true origins are now widely debated. In this review we discuss the different proposed mechanisms of the generation of both types of MDSCs, with a special focus on human MDSCs in cancer.
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| 11. |
- Rydberg Millrud, Camilla
(författare)
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Pattern-recognition receptors and neutrophils in cancer inflammation
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic inflammation, induced by the use of tobacco and alcohol, or caused by infections has long been suggested to constitute a risk factor for head and neck squamous cell carcinoma (HNSCC). The innate immunity is the first line of defense against pathogens, comprising physical and chemical barriers, anti-microbial peptides, pattern-recognition receptors (PRRs) as well as different kinds of cells, including neutrophils. Among the PRRs, Toll-like receptors (TLRs) and Nucleotide oligomerization domain (Nod)-like receptors (NLRs) have gained much attention. They both recognize viruses and bacteria. In addition to their protective role against infections, accumulating evidence suggests a role for these receptors in cancer. Neutrophils are among the first cells to migrate into an inflamed tissue, and their role in various infections is well described. Several studies have demonstrated anti-tumor activities of these cells, but they are also believed to have a tumor-promoting role. Recent data indicate the existence of three distinct neutrophil subsets, CD16dim CD62Lhigh, CD16high CD62Lhigh, and CD16high CD62Ldim cells, with diverse roles in infection, inflammation and cancer. The overall aim with this thesis was to investigate the potential role of PRRs and neutrophils in HNSCC. The thesis demonstrated that the HNSCC cells exhibited high levels of TLR2, TLR3, and TLR5, and a diverse NLR expression. Stimulation of TLR2, TLR3, TLR5, and Nod1 induced a robust inflammatory response and cell death in HNSCC cells that differed from what was seen in corresponding healthy epithelial cells. Following PRR stimulation the cancer cells up-regulated their expression of ICAM-1, and TLR activation increased the secretion of IL-1β, IL-6, and IL-8. In contrast, Nod1 enhanced the production of G-CSF and GM-CSF in HNSCC cells. In addition, the TLRs also affected the survival of the malignant cells. Altogether, this strengthens the suggestion that PRRs might mediate receptor specific tumor effects that can be either anti- or pro-tumorigenic. In the present study of HNSCC, TLRs induced an anti-tumorigenic response, whereas Nod1 activation caused pro-tumorigenic effects. Generally, HNSCC patients had a higher level of leukocytes and specifically more neutrophils in blood than healthy controls. Consequently, the neutrophil/lymphocyte ratio was high in the cancer patients, and a high ratio predicted worse prognosis. The three different neutrophil subsets mentioned above were found in the circulation of patients with HNSCC. The cancer patients exhibited a higher percentage of CD16high CD62Ldim cells than the healthy controls. Among the HNSCC patients, individuals with a high percentage of CD16high CD62Ldim neutrophils had a better outcome. In addition, the CD16high CD62Ldim cells represented the most active neutrophil phenotype. Hence, it might be that these activated neutrophils have anti-tumorigenic properties, and therefore are more favorable for the survival of the HNSCC patients. Altogether this emphasizes the beneficence of having an ongoing process of neutrophil recruitment and activation in patients with HNSCC. Patients with allergic rhinitis (AR) and HNSCC were found to exhibit distinct immunological reactions. The allergic patients exhibited enhanced serum levels of both Th1 and Th2 cytokines. The same increase was also seen in supernatants from their cultured PBMC. In contrast, HNSCC patients had an increase in serum level of cytokines reflecting an innate immune reaction. PMN isolated from these patients showed a generally increased basal activation, and responded strongly to TLR stimulation. Further, tumor biopsies from HNSCC patients displayed a higher Nod2 mRNA expression than nasal biopsies from healthy controls and AR patients outside and during pollen season. All in all, the immune reaction among the allergic patients had an adaptive character with an enhanced T cell activity, whereas the immune reaction of the HNSCC patients was dominated by an innate immune response with suppressed T cells. It is therefore tempting to propose that the enhanced systemic adaptive immune response seen among patients with AR might protect against development of HNSCC. In summary, this thesis demonstrates a receptor specific expression and function of PRRs in HNSCC. It also reveals that the inflammation in HNSCC is dominated by innate immune activities, and that recruitment and activation of neutrophils is important for the survival of these patients. Consequently, the ability to muster a proper inflammatory reaction might be vital for the defense and survival in patient with HNSCC.
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| 12. |
- Rydberg Millrud, Camilla, et al.
(författare)
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The Activation Pattern of Blood Leukocytes in Head and Neck Squamous Cell Carcinoma Is Correlated to Survival
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:12
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Tidskriftsartikel (refereegranskat)abstract
- Head and neck squamous cell carcinoma (HNSCC) is known to cause substantial immunosuppression. The present study was designed to characterize blood leukocyte activation in HNSCC and to investigate if the individual activation pattern could be related to tumor progress and survival. The leukocyte activation profile of HNSCC patients and healthy controls was assessed with flow cytometry. HNSCC patients displayed increased numbers of monocytes, neutrophils and total leukocytes as well as an enhanced neutrophil/lymphocyte ratio. In addition, patients had a higher percentage of CD69(+), CD71(+) and CD98(+) T cell subsets and NK cells, and a reduced expression of L-selectin in CD14(high)CD16(+) monocytes and neutrophils, when compared to controls. These changes could be correlated to both tumor burden and spread to lymph nodes. Among the cancer patients an increased neutrophil/lymphocyte ratio, a low neutrophil and CD14(high) CD16(+) monocyte activation state and an elevated CD4/CD8 ratio were related to poor survival. In contrast, a high percentage of CD98(+) Th cells appeared to be associated with a better outcome. Taken together, the present data indicate that HNSCC causes activation of blood leukocytes and that the individual activation pattern can be linked to prognosis.
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| 13. |
- Tengroth, Lotta, et al.
(författare)
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Functional Effects of Toll-Like Receptor (TLR)3, 7, 9, RIG-I and MDA-5 Stimulation in Nasal Epithelial Cells.
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- The human nasal epithelium is an important physical barrier, and a part of the innate immune defense that protect against pathogens. The epithelial cells recognize microbial components by pattern-recognition receptors (PRRs), and thereby trigger an immune response. Even though TLR3, TLR7, TLR9, RIG-I and MDA-5 are all known to respond to viral stimulation, their potential role in chronic airway inflammation triggered by local cytokine release remains to be established.
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