| 1. |
- Björk Gunnarsdottir, Frida, et al.
(författare)
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Co-localization of CD169+ macrophages and cancer cells in lymph node metastases of breast cancer patients is linked to improved prognosis and PDL1 expression
- 2020
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Ingår i: OncoImmunology. - 2162-4011. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is the most common form of cancer in women worldwide. Although the survival among breast cancer patients has improved, there is still a large group of patients with dismal prognosis. One of the most important prognostic factors for poor prognosis is lymph node metastasis. Increasing knowledge concerning the lymph nodes of breast cancer patients indicates that they are affected by the primary tumor. In this study we show that presence of CD169+ subcapsular sinus macrophages in contact with lymph node metastases in breast cancer patients, is related to better prognosis after adjuvant tamoxifen treatment, but only in patients with PDL1+ primary tumors. This is in contrast to the prognostic effect of CD169+ primary tumor-associated macrophages (TAMs). We further show that CD169+ macrophages were spatially associated with expression of PDL1 on nearby cells, both in primary tumors and metastatic lymph node, although PDL1 expression in metastatic lymph node as such did not have further prognostic impact. Our data suggest that CD169+ resident lymph node macrophages have a unique function in targeting immune responses against breast cancer and should be further investigated in detail.
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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. |
- Gunnarsdóttir, Fríða Björk, et al.
(författare)
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Establishment of Melanoma Tumor Xenograft Using Single Cell Line Suspension and Co-injection of Patient-Derived T Cells in Immune-Deficient NSG Mice
- 2019
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Ingår i: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer New York. - 1940-6029. ; 1913, s. 207-215
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Tidskriftsartikel (refereegranskat)abstract
- When primary tumor cells are grown in vitro, they are exposed to an environment that is vastly different from the tumor environment they originate from. The in vitro environment can lack the three-dimensional structure of the tumor, other cell types present within the tumor microenvironment, and important growth factors. Humanized mouse models allow researchers to study primary tumor cells in a more natural environment. With further development of several strains of immune-deficient mice, the mouse model allows for observation of the patient-derived tumor xenograft (PDTX) growth alone as well as in the presence of a human immune system. We describe how this can be accomplished with injection of single cell suspension of melanoma tumor cells into immune-deficient NOD-scid IL2Rγnull (NSG) mice. We also describe how tumor cells and immune cells can be co-injected, using Winn assay, and the possibility to use that method to study immune therapies for cancer.
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| 4. |
- Gunnarsdóttir, Fríða Björk
(författare)
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Function of Innate Immune Cells in Breast Cancer
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tumor associated macrophages (TAMs) are key cells in creating an immunosuppressive tumor microenvironment (TME). In general, presence of TAMs is associated with worse outcome in cancer patients. Macrophages with anti-tumor effect can be found in the TME but are usually in minority. This thesis focuses on the role of innate immune cells, and especially macrophages, in breast cancer. In the first project we showed that pro-inflammatory macrophages downregulate estrogen receptor alpha (ERα) on breast cancer cells. We unveiled the molecular mechanism behind this, showing that TNF-α derived from macrophages inactivates transcription factor FOXO3a. Moreover, presence of TAMs in breast cancer tumors associated with ER negativity and worse prognosis in ERα+ patients. In projects two and three we shifted our focus towards CD169+ macrophages in lymph nodes (LN) and primary tumors (PT) of breast cancer patients. In project II we showed that presence of CD169+ macrophages in metastatic LN correlated with better prognosis, while presence of CD169+ macrophages in PT did not. Association with PD-L1 expression was found in both locations. In project III we saw that CD169+ TAMs are most likely monocyte derived in a type I IFN environment and display a unique pro-inflammatory phenotype and cytokine profile, but with immunosuppressive function. In a patient cohort they were associated with tertiary lymphoid structures and regulatory T cells, and therefore with worse prognosis.In conclusion, TAMs represent a broad spectrum of macrophages with unique origin, phenotype, and function. In this thesis we have added to the growing knowledge of these cells and their role in breast cancer. Not only does the type of cancer matter for their function, but further their location and surrounding environment within breast cancer.
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| 5. |
- Gunnarsdóttir, Frida Björk, et al.
(författare)
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Inflammatory macrophage derived TNFα downregulates estrogen receptor α via FOXO3a inactivation in human breast cancer cells
- 2020
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 390:1
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Tidskriftsartikel (refereegranskat)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.
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| 6. |
- Gunnarsdottir, Frida Björk, et al.
(författare)
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Serum immuno-oncology markers carry independent prognostic information in patients with newly diagnosed metastatic breast cancer, from a prospective observational study
- 2023
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 25
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Tidskriftsartikel (refereegranskat)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.
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| 7. |
- Källberg, Eva, et al.
(författare)
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AIRE is expressed in breast cancer TANs and TAMs to regulate the extrinsic apoptotic pathway and inflammation
- 2024
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Ingår i: Journal of Leukocyte Biology. - 1938-3673. ; 115:4, s. 664-678
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Tidskriftsartikel (refereegranskat)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.
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| 8. |
- Smith, Frida, 1973, et al.
(författare)
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Evaluating the implementation and use of the regional cancer plan in Western Sweden through concept mapping
- 2019
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Ingår i: International Journal for Quality in Health Care. - : Oxford University Press (OUP). - 1464-3677 .- 1353-4505. ; 31:7, s. G44-G52
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Tidskriftsartikel (refereegranskat)abstract
- Quality problem or issue: Within healthcare, policy documents are often used to strategically standardize, streamline or change how general health issues are managed for a specific patient group or treatment. Despite significant effort in developing policy and strategic planning documents, these may not have the intended impact and their value has long been questioned by practitioners. Choice of solution: To identify barriers and affordances for the implementation and use of a strategic plan for cancer care in the Western Sweden Healthcare Region, we used Concept Mapping; a participatory mixed method approach to inquiry consisting of both qualitative and quantitative tasks intended to elicit and integrate the diverse perspectives of multiple stakeholders. Implementation: The study was carried out between April and October 2017 and consisted of several sequential data collection steps: idea generation, sorting and rating ideas for importance and feasibility. Stakeholders from different levels and professions in cancercare participated, but the number varied in the separate steps of data collection: idea generation (n = 112), sorting (n = 16) and rating (n = 38). Evaluation: A concept map visualized seven areas that stakeholders throughout the cancer-care process considered necessary to address in order to enable the implementation of the plan. Skills provision was considered the most important cluster but also rated as least feasible. A consistent theme emerged that information, or lack thereof, might be a barrier for the plan being put into action to a greater extent in the cancer-care units. Nine actionable ideas rated highly on both importance and feasibility were presented as a go-zone. Lessons learned: Our results suggest that efforts might be better spent on ensuring information about and accessibility to strategic documents throughout the organization, rather than frequently updating them or producing new ones. Having sufficient skills provision seems to be the prerequisite for successful implementation.
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| 9. |
- Smith, Frida, 1973, et al.
(författare)
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Exploring the meaning, role and experiences of a patient-led social innovation for people affected by cancer: a new collaborative care model complementing traditional cancer rehabilitation in Sweden
- 2021
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Ingår i: BMJ open quality. - : BMJ. - 2399-6641. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Objective Kraftens Hus is the first support centre in Sweden designed by and for people affected by cancer, including patients, family, friends, staff members and local community representatives (collectively 'stakeholders'). The purpose of this study was to explore the meaning, role and experiences of Kraftens Hus stakeholders using a patient and public involved methodology. Methods To understand and map the experiences of visitors to Kraftens Hus, we applied concept mapping (CM), a mixed methods approach where data are collected and analysed in four structured steps designed to capture the diverse perspectives of multiple stakeholders. Qualitative interviews with relevant stakeholders supplemented the CM findings. Results The final concept map contained six clusters of ideas. Within the clusters, there was a recurring theme that cancer-affected people value accessible and long-term psychosocial support (PSS). The intended emotional, social and practical needs identified in a previous design process seem to have been addressed and appreciated by Kraftens Hus visitors. Conclusion Kraftens Hus is an example of a new patient-led social innovation based on a life-event perspective and integration of resources from different sectors in society. By focusing on life, not the disease, the care continuum expands, and long-term PSS is provided alongside cancer treatment. The evaluation confirms that PSS should focus on health and well-being in the broadest sense.
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