SwePub - search: WFRF:(Bergenfelz Caroline)

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1.	Allaoui, Roni, et al. (author) Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers 2016 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Journal article (peer-reviewed)abstract Triple-negative (TN) breast cancers (ER â ' PR â ' HER2 â ') are highly metastatic and associated with poor prognosis. Within this subtype, invasive, stroma-rich tumours with infiltration of inflammatory cells are even more aggressive. The effect of myeloid cells on reactive stroma formation in TN breast cancer is largely unknown. Here, we show that primary human monocytes have a survival advantage, proliferate in vivo and develop into immunosuppressive myeloid cells expressing the myeloid-derived suppressor cell marker S100A9 only in a TN breast cancer environment. This results in activation of cancer-associated fibroblasts and expression of CXCL16, which we show to be a monocyte chemoattractant. We propose that this migratory feedback loop amplifies the formation of a reactive stroma, contributing to the aggressive phenotype of TN breast tumours. These insights could help select more suitable therapies targeting the stromal component of these tumours, and could aid prediction of drug resistance.
2.	Bergenfelz, Caroline, et al. (author) Clinical relevance of systemic monocytic-MDSCs in patients with metastatic breast cancer 2020 In: Cancer Immunology, Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 69:3, s. 435-448 Journal article (peer-reviewed)abstract The overall aim of this prospective study was to delineate the role of monocytic myeloid-derived suppressor cells (Mo-MDSCs) in patients with metastatic breast cancer (MBC). MDSCs are a heterogeneous group of immunosuppressive cells often enriched in different malignancies which hold prognostic and predictive value for clinical outcomes. Here, we assessed the clinical significance of Mo-MDSCs in 54 patients with de novo or distant recurrent MBC. We show that high levels of Mo-MDSCs significantly correlated with de novo MBC (metastatic disease at initial diagnosis), estrogen receptor (ER) negativity, and liver- and bone metastasis. A trend towards an association between high levels of Mo-MDSCs and survival (P = 0.053) was also found in patients with distant recurrent ER-positive MBC. We therefore propose that an increased population of Mo-MDSCs may be related to the metastatic or immunoregulatory switch associated with transition to a more systemic disease. Our data imply that high levels of systemic Mo-MDSCs represent patients with more aggressive disease and worse outcome.
3.	Bergenfelz, Caroline (author) Immunosuppressive Myeloid Cells in Breast Cancer and Sepsis 2014 Doctoral thesis (other academic/artistic)abstract Immune cells play paradoxical roles in cancer progression. On one hand, the immune system protects us against tumor development by recognizing and eliminating cancerous cells. On the other hand, tumor-associated immune cells can contribute to tumor progression by secreting growth factors as well as immunosuppressive, pro-angiogenic and/or pro-metastatic mediators. In this thesis we identified a factor (Wnt5a) that may be involved in skewing immune responses towards immunosuppressive, tumor promoting immune cell populations. In a pro-inflammatory setting (i.e. in the presence of exogenous pathogen-associated molecular patterns; PAMPs, or endogenous damage-associated molecular patterns; DAMPs), Wnt5a promoted the generation of immunosuppressive monocytes (CD14+HLA-DRlow/-Co-receptorlow/-). This was at the expense of generation of pro-inflammatory macrophages (M1). In addition, Wnt5a inhibited monocyte to dendritic cell differentiation (Mo-mDC). When co-injecting monocytes from healthy blood donors with MCF-7 or MDA-MB-231 breast cancer cells (luminal A and basal-like, respectively) into immunodeficient mice, monocytes promoted the generation of an activated tumor stroma and were preferentially recruited to basal-like tumors. Furthermore, monocytes from breast cancer patients were affected early during the disease, gradually becoming reprogrammed towards a novel population of monocytic myeloid-derived suppressor cells (Mo-MDSCs). The gene-expression profile of cancer-derived monocytes was remarkably similar to that of reprogrammed immunosuppressive monocytes from patients with gram-negative sepsis. This suggests that Mo-MDSCs may be generated in a similar manner in cancer and sepsis (by reprogramming of monocytes towards an immunosuppressive phenotype). We finally propose that Mo-MDSCs and granulocytic MDSCs are preferentially induced by different PAMPs. Altogether, we conclude that myeloid cells are skewed towards an immunosuppressive and tissue remodeling phenotype early during breast cancer. This resembles the situation during severe infections such as sepsis and most likely has a positive impact on tumor progression.
4.	Bergenfelz, Caroline, et al. (author) S100A9 expressed in ER(-)PgR(-) breast cancers induces inflammatory cytokines and is associated with an impaired overall survival. 2015 In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 113:8, s. 1234-1243 Journal article (peer-reviewed)abstract Breast cancer is the most common cancer form among women today. Depending on hormone receptor status, breast cancers are divided into different subtypes with vastly varying prognosis. S100A9 is a calcium-binding protein that is associated with inflammation and expressed not only in myeloid cells but also in some tumours. The role for S100A9 in the malignant cells is not well characterised; however, previous studies have shown that the protein could have important immune-modulating properties.
5.	Bergenfelz, Caroline, et al. (author) Streptococcus pneumoniae Otitis Media Pathogenesis and How It Informs Our Understanding of Vaccine Strategies. 2017 In: Current Otorhinolaryngology Report. - : Springer Science and Business Media LLC. - 2167-583X. ; 5:2, s. 115-124 Research review (peer-reviewed)abstract Purpose of Review This study aimed to review the literature regarding the mechanisms of transition from asymptomatic colonization to induction of otitis media and how the insight into the pathogenesis of otitis media has the potential to help design future otitis media-directed vaccines. Recent Findings Respiratory viruses have long been shown to predispose individuals to bacterial respiratory infections, such as otitis media. Recent information suggests that Streptococcus pneumoniae, which colonize the nasopharynx asymptomatical- ly, can sense potentially “threatening” changes in the nasopha- ryngeal environment caused by virus infection by upregulating specific sets of genes involved in biofilm release, dissemination from the nasopharynx to other sites, and protection against the host immune system. Furthermore, an understanding of the transcriptional and proteomic changes occurring in bacteria dur- ing transition to infection has led to identification of novel vaccine targets that are disease-specific and will not affect asymptomatic colonization. This approach will avoid major changes in the delicate balance of microorganisms in the respi- ratory tract microbiome due to elimination of S. pneumoniae. Summary Our recent findings are reviewed in the context of the current literature on the epidemiology and pathogenesis of otitis media. We also discuss how other otopathogens, such as Haemophilus influenzae and Moraxella catarrhalis, as well as the normal respiratory microbiome, can modulate the ability of pneumococci to cause infection. Furthermore, the unsatis- factory protection offered by the pneumococcal conjugate vaccines is highlighted and we review potential future strate- gies emerging to confer a more specific protection against otitis media.
6.	Bergenfelz, Caroline, et al. (author) Systemic Monocytic-MDSCs Are Generated from Monocytes and Correlate with Disease Progression in Breast Cancer Patients. 2015 In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5 Journal article (peer-reviewed)abstract Myeloid-derived suppressor cells (MDSCs) are highly immunosuppressive myeloid cells, which increase in cancer patients. The molecular mechanism behind their generation and function is unclear. Whereas granulocytic-MDSCs correlate with poor overall survival in breast cancer, the presence and relevance of monocytic-MDSCs (Mo-MDSCs) is unknown. Here we report for the first time an enrichment of functional blood Mo-MDSCs in breast cancer patients before they acquire a typical Mo-MDSC surface phenotype. A clear population of Mo-MDSCs with the typical cell surface phenotype (CD14+HLA-DRlow/-CD86low/-CD80low/-CD163low/-) increased significantly first during disease progression and correlated to metastasis to lymph nodes and visceral organs. Furthermore, monocytes, comprising the Mo-MDSC population, from patients with metastatic breast cancer resemble the reprogrammed immunosuppressive monocytes in patients with severe infections, both by their surface and functional phenotype but also at their molecular gene expression profile. Our data suggest that monitoring the Mo-MDSC levels in breast cancer patients may represent a novel and simple biomarker for assessing disease progression.
7.	Bergenfelz, Caroline, et al. (author) The Generation and Identity of Human Myeloid-Derived Suppressor Cells 2020 In: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 10 Research review (peer-reviewed)abstract Myeloid-derived suppressor cells (MDSCs) are cells of myeloid lineage with a potent immunosuppressive capacity. They are present in cancer patients as well as in patients with severe inflammatory conditions and infections. MDSCs exist as two main subtypes, the granulocytic (G-MDSCs) and the monocytic (Mo-MDSCs) type, as defined by their surface phenotype and functions. While the functions of MDSCs have been investigated in depth, the origin of human MDSCs is less characterized and even controversial. In this review, we recapitulate theories on how MDSCs are generated in mice, and whether this knowledge is translatable into human MDSC biology, as well as on problems of defining MDSCs by their immature cell surface phenotype in relation to the plasticity of myeloid cells. Finally, the challenge of pharmacological targeting of MDSCs in the future is envisioned.
8.	Bergenfelz, Caroline, et al. (author) Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients. 2012 In: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 188:11, s. 5448-5458 Journal article (peer-reviewed)abstract A well-orchestrated inflammatory reaction involves the induction of effector functions and, at a later stage, an active downregulation of this potentially harmful process. In this study we show that under proinflammatory conditions the noncanonical Wnt protein, Wnt5a, induces immunosuppressive macrophages. The suppressive phenotype induced by Wnt5a is associated with induction of IL-10 and inhibition of the classical TLR4-NF-κB signaling. Interestingly, this phenotype closely resembles that observed in reprogrammed monocytes in sepsis patients. The Wnt5a-induced feedback inhibition is active both during in vitro LPS stimulation of macrophages and in patients with sepsis caused by LPS-containing, Gram-negative bacteria. Furthermore, using breast cancer patient tissue microarrays, we find a strong correlation between the expression of Wnt5a in malignant epithelial cells and the frequency of CD163(+) anti-inflammatory tumor-associated macrophages. In conclusion, our data point out Wnt5a as a potential target for an efficient therapeutic modality in severe human diseases as diverse as sepsis and malignancy.
9.	Bergenfelz, Caroline, et al. (author) Wnt5a inhibits human monocyte derived myeloid dendritic cell generation. 2013 In: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 78:2, s. 194-204 Journal article (peer-reviewed)abstract Wnt5a is a non-canonical Wnt protein that is expressed at elevated levels in inflammatory conditions. Its role in inflammation remains unclear, although it is known that Wnt5a is expressed at a higher level in monocyte-derived myeloid dendritic cells (Mo-mDCs) than in monocytes and macrophages. The function of Wnt5a in dendritic cells (DCs) remains relatively unexplored. Here, we found that under Mo-mDC culture conditions, Wnt5a inhibited the generation of CD14(+/low) Mo-mDCs while promoting the generation of CD14(+/++) CD16(+) monocytes. We could further show that stimulation of monocytes with rWnt5a induced a rapid IL-6 production and that the rWnt5a treated Mo-mDC differentiation was restored upon blocking of IL-6. Also conditioned media from Wnt5a stimulated human breast cancer cells producing IL-6, specifically inhibited Mo-mDC differentiation. These observations are strengthened by our finding that patients with sepsis, a disease involving elevated Wnt5a and IL-6 levels, also showed a significant increase in the CD14(+) CD16(++) /CD14(+/++) CD16(+) monocyte populations, which was accompanied by a significant decrease in circulating mDCs. We finally show that under typical Mo-mDC culture conditions, monocytes isolated from sepsis patients as compared to healthy controls, preferentially differentiated into CD14(+/++) HLA-DR(++) cells. We suggest that Wnt5a is a possible candidate mediator for the CD14(+/++) CD16(+) monocyte accumulation seen in infectious disease and cancer patients. This article is protected by copyright. All rights reserved.
10.	Chao, Yashuan, et al. (author) Growing and Characterizing Biofilms Formed by Streptococcus pneumoniae 2019 In: Streptococcus pneumoniae : Methods and Protocols - Methods and Protocols. - New York, NY : Springer New York. - 1940-6029. - 9781493991990 - 9781493991983 ; 1968, s. 147-171 Book chapter (peer-reviewed)abstract It is estimated that over 80% of bacterial infections are associated with biofilm formation. Biofilms are organized bacterial communities formed on abiotic surfaces, such as implanted or inserted medical devices, or on biological surfaces, such as epithelial linings and mucosal surfaces. Biofilm growth is advantageous for the bacterial organism as it protects the bacteria from antimicrobial host factors and allows the bacteria to reside in the host without causing excessive inflammation. Like many other opportunistic pathogens of the respiratory tract, Streptococcus pneumoniae forms biofilms during asymptomatic carriage, which promotes, among other things, persistence in the niche, intraspecies and interspecies communication, and spread of bacterial DNA. Changes within the colonizing environment resulting from host assaults, such as virus infection, can induce biofilm dispersion where bacteria leave the biofilm and disseminate to other sites with ensuing infection. In this chapter, we present methodology to form complex biofilms in the nasopharynx of mice and to evaluate the biofilm structure and function in this environment. Furthermore, we present methods that recapitulate this biofilm phenotype in vitro by incorporating crucial factors associated with the host environment and describe how these models can be used to study biofilm function, transformation, and dispersion.
11.	Chao, Yashuan, et al. (author) In vitro and in vivo biofilm formation by pathogenic streptococci 2017 In: Methods in Molecular Biology. - New York, NY : Springer New York. - 1064-3745. ; 1535, s. 285-299 Book chapter (peer-reviewed)abstract This manuscript presents novel approaches to grow and evaluate Streptococcal biofilm formation using the human respiratory pathogen Streptococcus pneumoniae (the pneumococcus) as the main model organism on biological surfaces in vitro and in vivo. Most biofilm models are based on growth on abiotic surfaces, which is relevant for many pathogens whose growth on surfaces or medical devices is a major cause of disease transmission and infections, especially in hospital environments. However, most infections with commensal organisms require biofilm formation on biological surfaces in the host at the site of colonization or infection. In vitro model systems incorporating biological components from the host and taking into account the host environment of the infectious site are not well described. In a series of publications, we have shown that S. pneumoniae form complex biofilms in the nasopharynx of mice and have devised methodology to evaluate the biofilm structure and function in this environment. We have also been able to recapitulate this biofilm phenotype in vitro by incorporating crucial factors associated with the host environment. Although the protocols presented in this manuscript are focused on S. pneumoniae, the same methodology can and has been used for other Streptococcal species that form biofilms on mucosal surfaces.
12.	Chao, Yashuan, et al. (author) The serine protease HtrA plays a key role in heat-induced dispersal of pneumococcal biofilms 2020 In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1 Journal article (peer-reviewed)abstract Streptococcus pneumoniae (the pneumococcus) colonizes the human nasopharynx by forming multicellular biofilms. Due to the high level of asymptomatic carriage, transition to infections, such as otitis media, pneumonia, sepsis, and meningitis, occurs often enough that the pneumococcus remains a major cause of disease and death globally. Virus infection and virus-induced responses, such as increased temperature (fever), trigger release of virulent bacteria from colonizing biofilms. The exact mechanisms involved in pneumococcal egress during biofilm dispersal remain unknown, although we hypothesize that disruption of the biofilm matrix encasing the bacteria is necessary. Here, we utilized established in vitro biofilm dispersal models to investigate the involvement of proteases in bacterial egress from pneumococcal biofilms. We demonstrate the importance of protease activity, both through increased bacterial release following addition of proteases and reduced heat-induced biofilm dispersal in the presence of protease inhibitors. We identify a key role for the surface-exposed serine protease HtrA, but not PrtA, in heat-induced biofilm dispersal. Bacterial release from htrA-negative biofilms was significantly reduced compared to wild-type isogenic strains but was restored and increased above wild-type levels following addition of recombinant HtrA. Understanding the specific mechanisms involved in bacterial egress may provide novel targets for future strategies aimed to specifically interfere with disease progression without disturbing nasopharyngeal biofilm colonization.
13.	Dryver, Eric, et al. (author) Medical crisis checklists in the emergency department : a simulation-based multi-institutional randomised controlled trial 2021 In: BMJ Quality and Safety. - : BMJ. - 2044-5415 .- 2044-5423. ; 30:9, s. 697-705 Journal article (peer-reviewed)abstract Background: Studies carried out in simulated environments suggest that checklists improve the management of surgical and intensive care crises. Whether checklists improve the management of medical crises simulated in actual emergency departments (EDs) is unknown. Methods: Eight crises (anaphylactic shock, life-threatening asthma exacerbation, haemorrhagic shock from upper gastrointestinal bleeding, septic shock, calcium channel blocker poisoning, tricyclic antidepressant poisoning, status epilepticus, increased intracranial pressure) were simulated twice (once with and once without checklist access) in each of four EDs - of which two belong to an academic centre - and managed by resuscitation teams during their clinical shifts. A checklist for each crisis listing emergency interventions was derived from current authoritative sources. Checklists were displayed on a screen visible to all team members. Crisis and checklist access were allocated according to permuted block randomisation. No team member managed the same crisis more than once. The primary outcome measure was the percentage of indicated emergency interventions performed. Results: A total of 138 participants composing 41 resuscitation teams performed 76 simulations (38 with and 38 without checklist access) including 631 interventions. Median percentage of interventions performed was 38.8% (95% CI 35% to 46%) without checklist access and 85.7% (95% CI 80% to 88%) with checklist access (p=7.5×10-8). The benefit of checklist access was similar in the four EDs and independent of senior physician and senior nurse experience, type of crisis and use of usual cognitive aids. On a Likert scale of 1-6, most participants agreed (gave a score of 5 or 6) with the statement 'I would use the checklist if I got a similar case in reality'. Conclusion: In this multi-institution study, checklists markedly improved local resuscitation teams' management of medical crises simulated in situ, and most personnel reported that they would use the checklists if they had a similar case in reality.
14.	Ekström, Elin, et al. (author) WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells 2014 In: Molecular Cancer. - : Springer Science and Business Media LLC. - 1476-4598. ; 13 Journal article (peer-reviewed)abstract Background: Wnt proteins are important for developmental processes and certain diseases. WNT5A is a non-canonical Wnt protein that previously has been shown to play a role in the progression of malignant melanoma. High expression of WNT5A in melanoma tumors correlates to formation of distant metastasis and poor prognosis. This has partly been described by the findings that WNT5A expression in melanoma cell lines increases migration and invasion. Methods: Malignant melanoma cell lines were treated with rWNT5A or WNT5A siRNA, and mRNA versus protein levels of soluble mediators were measured using RT-PCR, cytokine bead array and ELISA. The induced signaling pathways were analyzed using inhibitors, Rho-GTPase pull down assays and western blot. Ultracentrifugation and electron microscopy was used to analyze microvesicles. Gene expression microarray data obtained from primary malignant melanomas was used to verify our data. Results: We show that WNT5A signaling induces a Ca2+-dependent release of exosomes containing the immunomodulatory and pro-angiogenic proteins IL-6, VEGF and MMP2 in melanoma cells. The process was independent of the transcriptional machinery and depletion of WNT5A reduced the levels of the exosome-derived proteins. The WNT5A induced exosomal secretion was neither affected by Tetanus toxin nor Brefeldin A, but was blocked by the calcium chelator Bapta, inhibited by a dominant negative version of the small Rho-GTPase Cdc42 and was accompanied by cytoskeletal reorganization. Co-cultures of melanoma/endothelial cells showed that depletion of WNT5A in melanoma cells decreased endothelial cell branching, while stimulation of endothelial cells with isolated rWNT5A-induced melanoma exosomes increased endothelial cell branching in vitro. Finally, gene expression data analysis of primary malignant melanomas revealed a correlation between WNT5A expression and the angiogenesis marker ESAM. Conclusions: These data indicate that WNT5A has a broader function on tumor progression and metastatic spread than previously known; by inducing exosome-release of immunomodulatory and pro-angiogenic factors that enhance the immunosuppressive and angiogenic capacity of the tumors thus rendering them more aggressive and more prone to metastasize.
15.	Enoksson, Frida, et al. (author) Niche- and gender-dependent immune reactions in relation to the microbiota profile in pediatric patients with otitis media with effusion 2020 In: Infection and Immunity. - 1098-5522. ; 88:10 Journal article (peer-reviewed)abstract Otitis media with effusion (OME) is a common inflammatory disease, primarily affecting children. OME is defined as a chronic low-grade inflammation of the middle ear (ME), without any signs of infection and with effusion persisting in the ME for more than three months. The precise pathogenesis is, however, not fully understood. Here, we comprehensively characterized and compared the host immune responses (inflammatory cells and mediators) and the overall microbial community composition (microbiota) present in matched middle ear effusion samples (MEE), external ear canal lavages, and nasopharynx (NPH) samples from children with OME. Female patients had significantly increased percentages of T lymphocytes and higher levels of a wide array of inflammatory mediators in their MEEs compared to male patients, which was unrelated to microbiota composition. The relative abundances of identified microorganisms were strongly associated with their niche of origin. Furthermore, specific inflammatory mediators were highly correlated with certain bacterial species. Interestingly, some organisms displayed a niche-driven inflammation pattern, where presence of Haemophilus spp and Corynebacterium propinquum in MEEs was accompanied by pro-inflammatory mediators, whereas their presence in NPH was accompanied by anti-inflammatory mediators. For Turicella and Alloiococcus we found exactly the opposite results, i.e., an anti-inflammatory profile when present in MEEs, whereas their presence in the NPH was accompanied by a pro-inflammatory profile. Altogether, our results indicate that immune responses in children with OME are highly niche- and microbiota-driven, but gender-based differences were also observed, providing novel insight into potential pathogenic mechanisms behind OME.
16.	Gunnarsdóttir, Frida Björk, et al. (author) Inflammatory macrophage derived TNFα downregulates estrogen receptor α via FOXO3a inactivation in human breast cancer cells 2020 In: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 390:1 Journal article (peer-reviewed)abstract Patients with estrogen receptor α positive (ERα+) breast cancer can respond to endocrine therapy, but treatment resistance is common and associated with downregulation of ERα expression in the dormant residual cells. Here we show, using long-term NSG xenograft models of human breast cancer and primary human monocytes, in vitro primary cell cultures and tumors from breast cancer patients, that macrophage derived tumor necrosis factor alpha (TNFα) downregulates ERα in breast cancer cells via inactivation of the transcription factor Forkhead box O transcription factor 3a (FOXO3a). Moreover, presence of tumor associated macrophages in the primary tumor of breast cancer patients, was associated with ERα negativity, and with worse prognosis in patients with ERα+ tumors. We propose that pro-inflammatory macrophages, despite being tumoricidal, may have direct effects on tumor progression and endocrine resistance in breast cancer patients. Our findings suggest that TNFα antagonists should be evaluated for treatment of ERα+ breast cancer.
17.	Gunnarsdottir, Frida Björk, et al. (author) Serum immuno-oncology markers carry independent prognostic information in patients with newly diagnosed metastatic breast cancer, from a prospective observational study 2023 In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 25 Journal article (peer-reviewed)abstract Background Metastatic breast cancer (MBC) is a challenging disease, and despite new therapies, prognosis is still poor for a majority of patients. There is a clinical need for improved prognostication where immuno-oncology markers can provide important information. The aim of this study was to evaluate serum immuno-oncology markers in MBC patients and their respective relevance for prediction of survival.Patients and methods We investigated a broad panel of 92 immuno-oncology proteins in serum from 136 MBC patients included in a prospective observational study (NCT01322893) with long-term follow-up. Serum samples were collected before start of systemic therapy and analyzed using multiplex proximity extension assay (Olink Target 96 Immuno-Oncology panel). Multiple machine learning techniques were used to identify serum markers with highest importance for prediction of overall and progression-free survival (OS and PFS), and associations to survival were further evaluated using Cox regression analyses. False discovery rate was then used to adjust for multiple comparisons.Results Using random forest and random survival forest analyses, we identified the top nine and ten variables of highest predictive importance for OS and PFS, respectively. Cox regression analyses revealed significant associations (P < 0.005) of higher serum levels of IL-8, IL-10 and CAIX with worse OS in multivariable analyses, adjusted for established clinical prognostic factors including circulating tumor cells (CTCs). Similarly, high serum levels of IL-8, IL-10, ADA and CASP8 significantly associated with worse PFS. Interestingly, high serum levels of FasL significantly associated with improved OS and PFS. In addition, CSF-1, IL-6, MUC16, TFNSFR4 and CD244 showed suggestive evidence (P < 0.05) for an association to survival in multivariable analyses. After correction for multiple comparisons, IL-8 still showed strong evidence for correlation to survival.Conclusion To conclude, we found six serum immuno-oncology markers that were significantly associated with OS and/or PFS in MBC patients, independently of other established prognostic factors including CTCs. Furthermore, an additional five serum immuno-oncology markers provided suggestive evidence for an independent association to survival. These findings highlight the relevance of immuno-oncology serum markers in MBC patients and support their usefulness for improved prognostication.
18.	Hakansson, Anders P., et al. (author) Low NF-κB activation and necroptosis in alveolar macrophages : A new virulence property of streptococcus pneumonia 2017 In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 216:4, s. 402-404 Journal article (peer-reviewed)
19.	Janols, Helena, et al. (author) A high frequency of MDSCs in sepsis patients, with the granulocytic subtype dominating in gram-positive cases. 2014 In: Journal of Leukocyte Biology. - 1938-3673. ; 96:5, s. 685-693 Journal article (peer-reviewed)abstract The causative microorganisms dictate the type of MDSC generated in sepsis patients, and a large proportion of PMN-MDSCs in gram-positive sepsis includes immunosuppressive myeloid blasts. MDSCs constitute a heterogeneous population of immature myeloid cells that potently suppress immune responses. They were identified originally in cancer patients and have since been reported to occur also in chronic inflammation, autoimmunity, and even bacterial infections. Human MDSCs are commonly divided into Mo-MDSCs and granulocytic (PMN-MDSCs) subtypes. To what extent the bona fide cancer MDSCs are representative of the proposed MDSCs found in other diseases is not well known. PMN-MDSCs have been found previously to be enriched among LDGs in density gradient-centrifuged blood. In this study, we analyzed potential MDSCs in sepsis patients with different causative microorganisms, using total peripheral blood compared with density gradient-centrifuged blood. We found a high frequency of typical CD14(+)HLA-DR(low) Mo-MDSCs in all sepsis patients, whereas the typical PMN-MDSCs, as well as a prominent CD14(low) PMN-MDSC-like population, appeared preferentially in gram-positive cases. The CD14(low) PMN-MDSC variant was demonstrated to suppress T cell proliferation in vitro via a ROS-dependent mechanism, to display an increased IL-10:TNF-α ratio, and to present with signs of immaturity: blast morphology and low cytokine levels. We conclude that a spectrum of cells with MDSC features is enriched in sepsis and that the microbial origin of sepsis contributes to the substantial interindividual patient variation in the MDSC pattern.
20.	Janols, Helena, et al. (author) Heterogeneity among septic shock patients in a set of immunoregulatory markers. 2014 In: European Journal of Clinical Microbiology & Infectious Diseases. - : Springer Science and Business Media LLC. - 1435-4373 .- 0934-9723. ; 33:3, s. 313-324 Journal article (peer-reviewed)abstract Immune activation is a regular feature of sepsis, but the incidence and nature of the ensuing inflammation-resolving and immunosuppressive component is less well understood. In this study, we compared immunoregulatory markers on blood leukocytes from patients with Gram-negative or Gram-positive sepsis or septic shock, and compared this to blood from patients with severe virosis or healthy controls. To this end, blood from 32 patients with sepsis, including ten cases with shock, and 12 patients with severe virosis were analysed by flow cytometry for the expression levels of monocyte HLA-DR, CD11c, CD14 and CD40, and for frequencies of CD163(+)-suppressive monocytes, HLA-DR(+) or CD40(+)-activated T cells and Tregs. Plasma cytokine levels were analysed as a functional measurement. Signs of immunosuppression dominated in the septic shock and Gram-positive sepsis groups, whereas monocyte activation was common in Gram-negative sepsis patients without shock. However, the main finding was the large inter-individual variation of immune activation and immunosuppression, with no correlation to prognosis among the shock patients. The pronounced inter-individual variation in the analysed monocyte and lymphocyte markers forms a strong argument that, when immunomodulatory treatment is considered in a sepsis patient, it should be personalised and guided by a detailed immune status assessment.
21.	Källberg, Eva, et al. (author) AIRE is expressed in breast cancer TANs and TAMs to regulate the extrinsic apoptotic pathway and inflammation 2024 In: Journal of Leukocyte Biology. - 1938-3673. ; 115:4, s. 664-678 Journal article (peer-reviewed)abstract Autoimmune regulator (AIRE) is a transcriptional regulator expressed in the thymus and necessary for maintaining immunological self-tolerance. Extra-thymic AIRE expression is rare and a role for AIRE in tumor-associated innate immune cells has not yet been established. In this study we show that AIRE is expressed in human pro-tumor neutrophils. In breast cancer, AIRE was primarily located to tumor associated neutrophils (TANs), and to a lesser extent to tumor associated macrophages (TAMs) and tumor cells. Expression of AIRE in TAN/TAMs, but not in cancer cells, was associated with an adverse prognosis. We show that the functional role for AIRE in neutrophils and macrophages is to regulate expression of immune mediators and the extrinsic apoptotic pathway involving the Fas/TNFR death receptors and Cathepsin G. We here propose that the role for AIRE in TAN/TAMs in breast tumors is to regulate cell death and inflammation, thus promoting tumor progression.
22.	Larsson, Anna Maria, et al. (author) Impact of systemic therapy on circulating leukocyte populations in patients with metastatic breast cancer 2019 In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1 Journal article (peer-reviewed)abstract Tumors affect the immune system, locally and systemically. The frequencies of specific circulating immune cell populations correlate with disease progression as well as prognosis of the patients. Although largely neglected, conventional antitumoral therapies often possess immunomodulatory properties and affect the levels of specific immune cell populations. Most information, however, derive from animal or in vitro studies. As this could impact prognosis as well as response to therapy, further studies of the effects of treatment on circulating immune cells in patients are warranted. In this pilot study, we evaluated a wide panel of circulating immune cells over time (up to six months) in ten patients with metastatic breast cancer receiving standard antitumoral regimens. Overall, endocrine therapy tends to enrich for natural killer (NK) and natural killer T (NKT) cells in the circulation, whereas both chemotherapy and endocrine therapy reduce the levels of circulating monocytic myeloid-derived suppressor cells (Mo-MDSCs). This indicates that the systemic immunosuppressive profile observed in patients tends to revert over the course of systemic therapy and holds promise for future combination treatment with standard antitumoral agents and immunotherapy.
23.	Larsson, Anna Maria, et al. (author) Peripheral Blood Mononuclear Cell Populations Correlate with Outcome in Patients with Metastatic Breast Cancer 2022 In: Cells. - : MDPI AG. - 2073-4409. ; 11:10 Journal article (peer-reviewed)abstract Local tumor-associated immune cells hold prognostic and predictive value in various forms of malignancy. The role of systemic, circulating leukocytes is, however, not well-characterized. In this prospective and explorative study, we aim to delineate the clinical relevance of a broad panel of circulating immune cells in 32 patients with newly diagnosed metastatic breast cancer (MBC) before the start of systemic treatment. Freshly isolated peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry and evaluated for potential associations to clinicopathological variables and patient outcome. We show that the levels of specific circulating leukocyte populations are associated with clinical parameters such as hormone receptor status, histological subtype, number of circulating tumor cells (CTCs) and metastatic burden. Importantly, high levels of CD8+ cytotoxic T lymphocytes (CTLs) are significantly linked to improved overall survival (OS). In patients with estrogen receptor (ER)-positive primary tumors, high levels of circulating CTLs and non-classical (CD14+CD16++) monocytes were associated with improved OS, whereas in patients with ER-negative tumors low levels of circulating natural killer (NK) cells potentially associate with improved OS. We propose that the levels of specific circulating immune cell populations, such as CD8+ CTLs, may be used to predict clinical outcomes in MBC patients. Thus, larger studies are warranted to validate these findings.
24.	Mehmeti-Ajradini, Meliha, et al. (author) Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer 2020 In: Life Science Alliance. - 2575-1077. ; 3:11 Journal article (peer-reviewed)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.
25.	Mehmeti-Ajradini, Meliha, et al. (author) Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer 2020 In: Life Science Alliance. - : LIFE SCIENCE ALLIANCE LLC. - 2575-1077. ; 3:11 Journal article (peer-reviewed)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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