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- 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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- Lagergren, Fredrik, et al.
(författare)
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Kilometre-scale simulations over Fennoscandia reveal a large loss of tundra due to climate warming
- 2024
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Ingår i: Biogeosciences. - 1726-4170 .- 1726-4189. ; 21:5, s. 1093-1116
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Tidskriftsartikel (refereegranskat)abstract
- The Fennoscandian boreal and mountain regions harbour a wide range of vegetation types, from boreal forest to high alpine tundra and barren soils. The area is facing a rise in air temperature above the global average and changes in temperature and precipitation patterns. This is expected to alter the Fennoscandian vegetation composition and change the conditions for areal land use such as forestry, tourism and reindeer husbandry. In this study we used a unique high-resolution (3 km) climate scenario with considerable warming resulting from strongly increasing carbon dioxide emissions to investigate how climate change can alter the vegetation composition, biodiversity and availability of suitable reindeer forage. Using a dynamical vegetation model, including a new implementation of potential reindeer grazing, resulted in simulated vegetation maps of unprecedented high resolution for such a long time period and spatial extent. The results were evaluated at the local scale using vegetation inventories and for the whole area against satellite-based vegetation maps. A deeper analysis of vegetation shifts related to statistics of threatened species was performed in six “hotspot” areas containing records of rare and threatened species. In this high-emission scenario, the simulations show dramatic shifts in the vegetation composition, accelerating at the end of the century. Alarmingly, the results suggest the southern mountain alpine region in Sweden will be completely covered by forests at the end of the 21st century, making preservation of many rare and threatened species impossible. In the northern alpine regions, most vegetation types will persist but shift to higher elevations with reduced areal extent, endangering vulnerable species. Simulated potential for reindeer grazing indicates latitudinal differences, with higher potential in the south in the current climate. In the future these differences will diminish, as the potentials will increase in the north, especially for the summer grazing grounds. These combined results suggest significant shifts in vegetation composition over the present century for this scenario, with large implications for nature conservation, reindeer husbandry and forestry.
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- Zimmermannova, Olga, et al.
(författare)
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Restoring tumor immunogenicity with dendritic cell reprogramming
- 2023
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Ingår i: Science Immunology. - 2470-9468. ; 8:85
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Tidskriftsartikel (refereegranskat)abstract
- Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8 + T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8 + T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.
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