| 1. |
- Altunbulakli, Can, et al.
(författare)
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Targeted spatial proteomic analysis of CD8+ T- and myeloid cells in tonsillar cancer
- 2023
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Ingår i: Frontiers in Oncology. - 2234-943X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tonsillar cancer is caused by high-risk human papillomavirus (HPV), tobacco smoking, and alcohol abuse. Aspects of the patient’s immune response to this disease have arisen as prognostic factors and treatment targets, reflecting differences in the type and protein expression profile of immune cells. Because tonsillar cancers are heterogenous lesions such data need to be spatially resolved. Methods: In this study, we aim to explore inter-patient and intra-tumoral sources of variation in tonsillar cancer using immunofluorescence and targeted spatial proteomics to interrogate a cohort of 105 patients. Furthermore, we assess prognostic factors and elucidate molecular targets. We have used CD8, CD11c, and Pan-cytokeratin (PanCK) to quantify and locate immune cells driving antigen-specific cellular immunity. Guided by immunofluorescence information, we selected 355 CD8+, CD11c+, or PanCK+ areas inside and outside (i.e., stroma) cancer-cell islets, to quantify 43 immune-related proteins using digital spatial profiling. Results: Quantitative analysis of immunofluorescence in combination with clinical data revealed that the abundance of total CD8+ cells and CD8+ cells infiltrating cancer-cell islets, respectively, were associated with higher 5-year disease-free survival and overall survival, independently of HPV-status and clinical stage. Comparison of CD8+ cells inside and outside cancer-cell islets revealed an upregulation of effector CD8+ T-cell and immune checkpoint molecules in the former. Among these, the expression of PD-L1 by CD8+ T-cells was associated with lower all-cause mortality in a univariate proportional hazards model. Similarly, a comparison of tumor boundary and stroma CD11c+ cells showed upregulation of both co-stimulatory and immune checkpoint molecules with proximity to tumor cell islets. Conclusion: Our findings highlight the relevance of analyzing aspects of tumor micro-architecture in the search of prognostic markers and molecular targets for tonsillar cancer. The abundance of intra-tumoral CD8+ T-cells can be considered a positive predictive marker for tonsillar cancer, while the significance of PD-L1 expression by intra-tumoral CD8+ T-cells warrants further evaluation. Location-based differences in CD8+ and CD11c+ cells suggest an immune cell-altering effect on the tumor microenvironment, and grant new insight into which cells that can be targeted by novel therapeutic agents.
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| 2. |
- Askmyr, David, et al.
(författare)
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Pattern recognition receptor expression and maturation profile of dendritic cell subtypes in human tonsils and lymph nodes
- 2021
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Ingår i: Human Immunology. - : Elsevier BV. - 0198-8859. ; 82:12, s. 976-981
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DCs) with capacity of antigen cross-presentation are of key interest for immunotherapy against cancer as they can induce antigen-specific cytotoxic T lymphocyte (CTL) responses. This study describes frequencies of DC subtypes in human tonsils and lymph nodes, and phenotypic aspects that may be targeted by adjuvant measures. From human tonsils and neck lymph nodes, DCs were identified through flow cytometry, and subsets of plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were investigated. Maturity status was assessed and surface receptors with CTL-promoting potentials were studied. CD123+ pDCs as well as CD1c+, CD141+, and CD1c-CD141- mDCs were detected in tonsils and lymph nodes. Both sites featured a similar presence of DC subsets, with CD123+ pDC being dominant and CD141+ mDCs least frequent. Based on CD80/CD86 expression, all DC subtypes featured a low degree of maturation. Expression of pattern recognition receptors (PRRs) CD206, CD207, DC-SIGN, TLR2, and TLR4, as well as the chemokine receptor XCR1, indicated DC subset-specific receptor profiles. We conclude that tonsils and lymph nodes share common features in terms of DC subset frequency and maturation as well as PRR and XCR1 expression pattern. Our work suggests that both sites may be considered for vaccine deposition in DC-mediated immunotherapy.
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| 3. |
- Gidhagen, Lars, et al.
(författare)
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Towards climate services for European cities : Lessons learnt from the Copernicus project Urban SIS
- 2020
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Ingår i: Urban Climate. - Amsterdam, Netherlands : Elsevier. - 2212-0955. ; 31
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Tidskriftsartikel (refereegranskat)abstract
- The growing share of Europe's population living in cities makes urban climate change impact assessment and adaptation a critical issue. The urban environment is characterized by its sensitivity to small-scale meteorological, hydrological and environmental processes. These are generally not fully described in climate models, largely because of the models' insufficient spatial resolution. The Urban SIS climate service offers historical and future simulated data downscaled to 1 km × 1 km resolution over selected European metropolitan areas. The downscaled data are subsequently used as input to air quality and hydrological impact models, all made available to users as Essential Climate Variables and Sectoral Impact Indicators through a web portal. This paper presents the Urban SIS climate service and demonstrates its functionality in a case study in Stockholm city, Sweden. Good model performance was attained for intra-city temperature gradients and small-scale precipitation extremes. Less positive results were obtained for large-scale precipitation and hydrology, mainly due to an insufficient domain size in the meteorological and climate modelling, in turn related to the substantial computational requirements. An uncertainty classification approach was developed to aid the interpretation and user application of the data. We hope our lessons learnt will support future efforts in this direction.
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| 4. |
- Gomez Jimenez, David, et al.
(författare)
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Single-cell analysis of myeloid cells in HPV+ tonsillar cancer
- 2022
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The incidence of Human Papillomavirus positive (HPV+) tonsillar cancer has been sharply rising during the last two decades. Myeloid cells represent an appropriate therapeutic target due to their ability to orchestrate antigen-specific immunity within the tonsil, the availability of viral antigens, and the proximity of the tumor and the underlying lymphoid tissue. However, the interrelationship of steady-state and inflammatory myeloid cell subsets, and their impact on patient survival remains unexplored. Here, we used single-cell RNA-sequencing to map the myeloid compartment in HPV+ tonsillar cancer. Our analysis unveiled the existence of four dendritic cell lineages, two macrophage polarization processes, and their sequential maturation profiles. We observed an expansion of the myeloid compartment in HPV+ tonsillar cancer, accompanied by interferon-induced cellular responses both in DCs and monocyte-macrophages. Within the DC lineages, we describe a balance shift in the frequency of progenitor and mature cDC favoring the cDC1 lineage in detriment of cDC2s, in HPV+ lesions. Furthermore, we observed that all DC lineages apart from DC5s matured into a common activated DC profile. In turn, the monocyte-macrophage lineage was subjected to early monocyte polarization events, which gave raise to inflammatory-activated, and chemokine-producing macrophages. We validated the existence of most of the single-cell RNA-seq clusters using 26-plex flow cytometry, and described a positive impact of cDC1, activated DCs and macrophages in patient survival using signature scoring. The current study contributes towards the understanding of myeloid ontogeny and dynamics in human papilloma driven tonsillar cancer, and details myeloid biomarkers that can be used to predict therapy effects and assess patient prognosis.
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| 5. |
- Jimenez, David Gomez, et al.
(författare)
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Single-cell analysis of myeloid cells in HPV+ tonsillar cancer
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of human papillomavirus-positive (HPV+) tonsillar cancer has been sharply rising during the last decades. Myeloid cells represent an appropriate therapeutic target due to their proximity to virus-infected tumor cells, and their ability to orchestrate antigen-specific immunity, within the tonsil. However, the interrelationship of steady-state and inflammatory myeloid cell subsets, and their impact on patient survival remains unexplored. Here, we used single-cell RNA-sequencing to map the myeloid compartment in HPV+ tonsillar cancer. We observed an expansion of the myeloid compartment in HPV+ tonsillar cancer, accompanied by interferon-induced cellular responses both in dendritic cells (DCs) and monocyte-macrophages. Our analysis unveiled the existence of four DC lineages, two macrophage polarization processes, and their sequential maturation profiles. Within the DC lineages, we described a balance shift in the frequency of progenitor and mature cDC favoring the cDC1 lineage in detriment of cDC2s. Furthermore, we observed that all DC lineages apart from DC5s matured into a common activated DC transcriptional program involving upregulation of interferon-inducible genes. In turn, the monocyte-macrophage lineage was subjected to early monocyte polarization events, which give rise to either interferon-activated or CXCL-producing macrophages, the latter enriched in advanced tumor stages. We validated the existence of most of the single-cell RNA-seq clusters using 26-plex flow cytometry, and described a positive impact of cDC1 and interferon-activated DCs and macrophages on patient survival using gene signature scoring. The current study contributes to the understanding of myeloid ontogeny and dynamics in HPV-driven tonsillar cancer, and highlights myeloid biomarkers that can be used to assess patient prognosis.
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| 6. |
- Jimenez, David Gomez, et al.
(författare)
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Tonsillar cancer with high cd8+ t‐cell infiltration features increased levels of dendritic cells and transcriptional regulation associated with an inflamed tumor microenvironment
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:21
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Tidskriftsartikel (refereegranskat)abstract
- Human papillomavirus (HPV) is the main causal agent of tonsillar cancer (TC) and HPV+ TC has a favorable prognosis compared to HPV– disease. In this study, we examined aspects of the tumor microenvironment of TC, focusing on T‐cells, dendritic cells (DC), and macrophages. Fresh biopsies of TC and the contralateral healthy tonsil (HT) were obtained from 20 patients, analyzed by multiparameter flow cytometry, and assessed against a detailed HPV‐status. Additionally, RNA-sequencing data from 38 TC samples available in the public database, The Cancer Genome Atlas (TCGA), were explored, focusing on the same leukocyte populations. HPV+ TC featured increased levels of CD8+ T‐cells and antigen‐presenting cells (cf. HPV– TC and HT, respectively). In HPV+ TC, CD8+ T‐cell frequencies correlated to DC levels independently of tumor stage, HPV 16 copy number, and E7 oncogene expression as well as frequencies of other leukocytes. Similarly, RNA sequencing data were explored by dividing the HPV+ TCs according to predefined CD8+ T‐cell scores in silico. Higher levels of genes expressed by antigen‐presenting cells and effector T‐cells, such as immune checkpoints and cytokines, were detected in the CD8HIGH HPV+ TC samples (cf. CD8LOW HPV+ TC). In conclusion, CD8HIGH HPV+ TC displays a unique inflammatory profile associated with increased effector T‐cell functions and the presence of antigen‐presenting cells in the tumor microenviron-ment. Further studies are warranted to assess if this information can be used on an individual basis to aid in prognosis and treatment decisions.
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| 7. |
- Abolhalaj, Milad, et al.
(författare)
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Profiling dendritic cell subsets in head and neck squamous cell tonsillar cancer and benign tonsils.
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:8030
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DCs) have a key role in orchestrating immune responses and are considered important targets for immunotherapy against cancer. In order to develop effective cancer vaccines, detailed knowledge of the micromilieu in cancer lesions is warranted. In this study, flow cytometry and human transcriptome arrays were used to characterize subsets of DCs in head and neck squamous cell tonsillar cancer and compare them to their counterparts in benign tonsils to evaluate subset-selective biomarkers associated with tonsillar cancer. We describe, for the first time, four subsets of DCs in tonsillar cancer: CD123+ plasmacytoid DCs (pDC), CD1c+, CD141+, and CD1c-CD141- myeloid DCs (mDC). An increased frequency of DCs and an elevated mDC/pDC ratio were shown in malignant compared to benign tonsillar tissue. The microarray data demonstrates characteristics specific for tonsil cancer DC subsets, including expression of immunosuppressive molecules and lower expression levels of genes involved in development of effector immune responses in DCs in malignant tonsillar tissue, compared to their counterparts in benign tonsillar tissue. Finally, we present target candidates selectively expressed by different DC subsets in malignant tonsils and confirm expression of CD206/MRC1 and CD207/Langerin on CD1c+ DCs at protein level. This study descibes DC characteristics in the context of head and neck cancer and add valuable steps towards future DC-based therapies against tonsillar cancer.
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| 8. |
- Ahlgren, Karin, et al.
(författare)
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De stora restaureringarna : Från Uppsala domkyrka till Skokloster
- 2004
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Rapport (populärvet., debatt m.m.)abstract
- De stora restaureringarna har varit årets tema. Genom att dokumentera och analysera teori och praktik i några av 1800- och 1900-talets största restaureringar - från genomgripande stilrestaureringar till ett mer återhållsamt och tekniskt skonsamt synsätt. Därmed får vi också ett bättre underlag även för dagens ställningstagande.Föremål för våra studier är Uppsala domkyrka, Gripsholms slott, Vreta klosterkyrka, Gustav 11I:s paviljong i Haga, Kungapalatset i Vadstena och Skoklosters slott. Vi hoppas att denna utställning skall bidra till en kritisk hållning och en ökad kunskap om restaureringskonsten, som kvalificerad yrkesuppgift, tidsspegel för historiesyn och som gestaltningsideal.
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| 9. |
- Andersson, Hampus, et al.
(författare)
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Early Pharmacodynamic Changes Measured Using RNA Sequencing of Peripheral Blood from Patients in a Phase I Study with Mitazalimab, a Potent CD40 Agonistic Monoclonal Antibody
- 2023
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Ingår i: Cells. - 2073-4409. ; 12:19
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Tidskriftsartikel (refereegranskat)abstract
- CD40-targeting therapies can enhance the dendritic cell priming of tumor-specific T cells and repolarize intratumoral macrophages to alleviate the tumoral immunosuppressive environment and remodel the extracellular matrix. Mitazalimab is a potent agonistic CD40 monoclonal IgG1 antibody currently under clinical development. This study used RNA sequencing of blood samples from a subset of patients from a Phase I trial with mitazalimab (NCT02829099) to assess peripheral pharmacodynamic activity. We found that mitazalimab induced transient peripheral transcriptomic alterations (at 600 µg/kg and 900 µg/kg dose administered intravenously), which mainly were attributed to immune activation. In particular, the transcriptomic alterations showed a reduction in effector cells (e.g., CD8+ T cells and natural killer cells) and B cells peripherally with the remaining cells (e.g., dendritic cells, monocytes, B cells, and natural killer cells) showing transcription profiles consistent with activation. Lastly, distinct patient subgroups based on the pattern of transcriptomic alterations could be identified. In summary, the data presented herein reinforce the anticipated mode of action of mitazalimab and support its ongoing clinical development.
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| 10. |
- Bulik, Cynthia M., et al.
(författare)
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SUBJECTIVE EXPERIENCES OF ANOREXIA NERVOSA IN PATIENTS WITH HIGH VS LOW ANOREXIA NERVOSA POLYGENIC RISK
- 2023
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Ingår i: European Neuropsychopharmacology. - : Elsevier. - 0924-977X .- 1873-7862. ; 75:Suppl. 1, s. S14-S14
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Recent genome-wide association studies (GWAS) suggest that genetic factors play a key role in its development and expression and that anorexia nervosa (AN) might have both psychiatric and metabolic underpinnings. One hypothesis is that those with high genetic vulnerability to AN may experience negative energy balance (NEB) (i.e., expending more energy than you consume) in a positive manner, rendering self-starvation and excessive exercise exceptionally reinforcing. This “paradoxical” response to NEB may also complicate recovery. In the Polygenic risk of Anorexia nervosa and its Clinical Expression (PACE) study, we explored differences in clinical and phenomenological/experiential phenotypes (i.e., how patients reported their experience of illness) in 10 individuals with AN who were in the top decile of AN polygenic risk (PRS) and 10 individuals with AN who were in the lowest decile in the Swedish subsample of the Anorexia Nervosa Genetics Initiative (ANGI) study. We interviewed the participants in a double-blind study design using a structured interview guide focusing on the experience of AN, including experiences of NEB (e.g., hunger, satiety, dietary restriction), the development of symptoms, as well as the reactions of others including family members and treatment providers to patients’ experiences of NEB. All interviews have been coded and the blind will be broken in May 2023 at which point group comparisons will be analyzed. This is the first study, to our knowledge, to explore experiential impact of genetic risk. Findings may aid in understanding risk, clinical course, and individual experience of AN and contribute suggestions for tailoring interventions with input from genetic risk profiles.
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