| 1. |
- Cabrita, Rita, et al.
(författare)
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Tertiary lymphoid structures improve immunotherapy and survival in melanoma
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 577:7791, s. 561-565
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Tidskriftsartikel (refereegranskat)abstract
- Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
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| 2. |
- Cabrita, Rita, et al.
(författare)
-
Tertiary lymphoid structures improve immunotherapy and survival in melanoma.
- 2020
-
Ingår i: Nature. - : Nature Publishing Group. - 1476-4687 .- 0028-0836. ; 577:7791, s. 561-565
-
Tidskriftsartikel (refereegranskat)abstract
- Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
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| 3. |
- Lövgren, Tanja, et al.
(författare)
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Complete and long-lasting clinical responses in immune checkpoint inhibitor-resistant, metastasized melanoma treated with adoptive T cell transfer combined with DC vaccination
- 2020
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Ingår i: Oncoimmunology. - : TAYLOR & FRANCIS INC. - 2162-4011 .- 2162-402X. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Development of T cell-directed immune checkpoint inhibitors (ICI) has revolutionized metastatic melanoma (MM) therapy, but <50% of treated patients experience durable responses. This phase I trial (NCT01946373) investigates the safety/feasibility of tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) combined with dendritic cell (DC) vaccination in MM patients progressing on ICI. An initial cohort (5 patients) received TIL therapy alone to evaluate safety and allow for optimization of TIL expansion protocols. A second cohort (first-in-man, 5 patients) received TIL combined with autologous tumor lysate-loaded DC vaccination. All patients received cyclophosphamide/fludarabine preconditioning prior to, and intravenous (i.v.) IL-2 after, TIL transfer. The DC vaccine was given as five intradermal injections after TIL and IL-2 administration. [F-18]-FDG PET/CT radiology was performed to evaluate clinical response, according to RECIST 1.1 (on the CT part). Immunological monitoring was performed by flow cytometry and T-cell receptor (TCR) sequencing. In the safety/optimization cohort, all patients had a mixed response or stable disease, but none durable. In the combination cohort, two patients experienced complete responses (CR) that are still ongoing (>36 and >18 months, respectively). In addition, two patients had partial responses (PR), one still ongoing (>42 months) with only a small bone-lesion remaining, and one of short duration (<4 months). One patient died early during treatment and did not receive DC. Long-lasting persistency of the injected TILs was demonstrated in blood. In summary, we report clinical responses by TIL therapy combined with DC vaccination in 4 out of 4 treated MM patients who previously failed ICI.
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| 4. |
- Miškovský, Karel, et al.
(författare)
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Utveckling av effektiva och relevanta metoder för bedömning av bergmaterial innehållande metallförande sulfidmineral
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Miljöanpassad hantering av sulfidförande bergmaterial kräver relevanta undersöknings-, provtagnings- och analysmetoder för bedömning av krossproduktens eventuella negativa miljöeffekter. Det föreliggande projektets mål var att på vetenskapliga grunder framställa, utvärdera och rekommendera praktiskt tillämpbara metoder för klassificering av bergmaterialens reaktivitet relaterad till innehåll av sulfidmineral. Projektet ska också föreslå metoder för behandling av bergmaterial där negativa miljöeffekter på närmiljön kan förutses.Projektet var indelat i sex delprojekt: 1) Översiktlig klassificering av sulfidförande berggrund, 2) Anrikning av sulfidmineral i samband med produktion av olika bergmaterialprodukter, 3) Utveckling och testning av effektiva och representativa provtagnings- och provhanteringsmetoder för fast berg och krossmaterial, 4) Val av relevanta och effektiva analysmetoder, 5) Framtagning av metod för klassificering av sulfidförande bergkross samt 6) Val, testning och verifiering av hållbara metoder för neutralisering av syrabildning från sulfidoxidation.Slutrapporten innehåller en sammanställning av delprojektens resultat med en systematisk presentation av metodik för effektiv bedömning, klassificering och behandling av sulfidförande bergmaterial och krossprodukter.
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| 5. |
- Mustafa, Majid, 1987-
(författare)
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Removal of Micropollutants from Wastewater : evaluation of effect of upgrading ozonation to electro-peroxone
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The United Nations (UN) has adopted 17 “Sustainable Development Goals” (SDGs) to achieve a clean, better and sustainable future. SDG 6 is to ensure that everyone has access to clean water and sanitation by 2030. According to the UN Educational, Scientific and Cultural Organization (UNESCO), more than 80% of wastewater produced from human actions is discharged into rivers or seas without any pollution removal. Thus, the presence of micropollutants (MPs: including, inter alia, pharmaceuticals, biocides and personal care products) in wastewaters is a major challenge that poses potential threats not only to aquatic system but also to humans due to their potential toxicity and potential to induce antibiotic resistance. Wastewater treatment plants (WWTPs) are considered hotspots for release of MPs as the current treatment processes are not designed to remove them. This thesis is based on studies described in four appended papers (Papers I-IV) designed to help efforts to solve these problems by investigating the factors involved and developing advanced treatment processes for removing MPs.Ozonation is one of the most intensively studied and widely used advanced treatment processes for removing MPs. However, due to ozone’s (O3) chemical selectivity, it cannot remove resistant MPs so its use (without additional treatments) results in their release into the environment. Thus, key objectives were to evaluate effects of switching to a new emerging process called electro-peroxone (E-peroxone) on MPs’ removal, by inserting two electrodes into an ozonation reactor. Its potential utility for other applications were also investigated.Paper I addresses effects of upgrading from ozonation to E-peroxone on pharmaceuticals’ removal at lab-scale, using a quantitative structure-activity relationship (QSAR) model. For this purpose, the relationship between QSAR model-predicted second-order rate constants of ozone’s reactions with pharmaceuticals (kO3 values) and ratios of experimentally determined pseudo-first order rate constants of E-peroxone and ozonation (kEP/kOZ values) was examined. Results showed that E-peroxone accelerated the removal of O3-resistant pharmaceuticals. In addition, the QSAR model predicted kO3 values for 491 pharmaceuticals, which suggested that large numbers of pharmaceuticals have high O3 resistance. Paper II addresses the removal of antimicrobials, including biocides and antibiotics, by E-peroxone and ozonation in relation to the water matrix. The results indicated that all studied antibiotics were effectively removed by both processes. In contrast, most of the biocides were at most moderately reactive with ozone, so their removal rate by ozonation was lower. The E-peroxone process increased their removal rate (i.e. removed them much more rapidly) by enhancing formation of hydroxyl radicals (•OH). Paper III reports the design, construction and tests of a pilot-scale mobile E-peroxone and ozonation system for removing naturally occurring MPs in secondary wastewater effluents. The tests included assessments of a new, scalable graphene modified carbon brush cathode for the E-peroxone process, which was found to enhance removal of moderately O3-reactive MPs significantly, and O3-resistant MPs moderately, while consuming similar amounts of electrical energy, or even less, for removing most of the MPs used in the experiments. Paper IV describes the regeneration of spent activated carbon, used for removing ionic MPs, by E-peroxone and ozonation. Both processes restored the activated carbon’s sorption efficiency to similar (or even higher) levels than that of virgin activated carbon, for all tested MPs except perfluorooctanoic acid (PFOA). It was concluded that sorption of MPs on regenerated activated carbon is mainly driven by interactions between ionic forms of the MPs with activated carbon’s charged surfaces rather than their interactions with pores in the activated carbon.
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| 6. |
- Paulsson, Oscar
(författare)
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Pit lake water quality and hydrology : Insights from case studies and modelling of pit lakes in northern Sweden
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- As extraction techniques are improving an increased number of low grade deposits can be economically mined. However, this also means that the number of open pit mines will increase and as a result the number of pit lakes as well. This is of environmental concern as the pit lakes, depending on the geology and other factors, potentially can have a negative impact on surrounding ecosystems, e.g. through high metal concentrations, low pH, and by affecting the hydrologic system. Sweden has a long history of mining and is one the largest metal suppliers in Europe, and many of the mines are located in the northern part of the country. The project aim was to better understand and be able to predict pit lake water quality and some of the underlying processes affecting it, with a focus on cold climates, where temperatures are low and the lakes are ice covered for prolonged periods of time. The following field measurements were conducted in the Laver and Åkerberg pit lakes: 1) minewall stations measuring metal leaching rates from pit walls, 2) oxygen and hydrogen isotopic composition of precipitation and pit lakes to better understand pit lake hydrology (including also the Udden and Rävlidmyran pit lakes), 3) a nutrient limitation and metal uptake experiment in the Åkerberg pit lake, and 4) a continuously measuring buoy installed in the Laver pit lake where short term fluctuations in water quality parameters could be observed. A bathymetric map of the Åkerberg pit lake was also generated during the project. Additionally, modelling of the Rävlidmyran pit lake was conducted based on three different climate scenarios. Measurements of water quality parameters showed that both the Laver and Åkerberg pit lakes have relatively good water quality, pH 6.1–7.4, specific conductivity 41–352 μS/cm and pH 7.6-7.7, specific conductivity 137–140 μS/cm, respectively, and low concentrations of metals. Algal growth was successfully stimulated in microcosms in the Åkerberg pit lake, through addition of the nutrients N and P in combination. Chlorophyll-a concentrations, which were used to estimate algal growth, were 9.5-11 times higher than at the beginning of the experiment in these microcosms. It was also seen that the metal concentration in the suspended particulate phase increased, suggesting that metals were taken up by algae. In the Laver pit lake measurements from the continuously measuring buoy showed diurnal variations for pH, dissolved oxygen, and temperature. The pH and dissolved oxygen was increasing during daytime, indicating that algal growth was increasing. A local meteoric water line, which can be used to separate sources of water from precipitation, if their isotopic compositions are different, was constructed for the study area (δ2H = (7.80 ± 0.09) δ18O + (4.35 ± 1.35) ‰). It was seen that the groundwater had a similar stable isotopic composition as precipitation, as its composition fell on the local meteoric water line. It was also seen that the studied pit lakes had undergone evaporation as they plotted on a local evaporation line (δ2H = (6.88 ± 0.47) δ18O + (−12.75 ± 5.60) ‰). Residence times were calculated for the pit lakes, ranging from 2.9-44.9 years, using the isotopic mass balance method. Modelling of the Rävlidmyran pit lake suggests that it is fairly stable and will remain meromictic during a modelled 100 year period. No major differences in redox or oxygen levels were observed. The temperature is predicted to increase in the mixolimnion along with a slight decrease in dissolved oxygen concentration. The modelling also indicates that the water outflow from the lake might increase, and as a consequence, a slight increase of metal outflow was observed as well. Based on minewall stations, installed at the Laver and Åkerberg mine sites, leaching rates (µg/m2/week) of metals were estimated. These were used to approximate the total contribution of metals from the pit walls to the pit lakes over the course of a year. A difference in metal leaching could be observed for the two mine sites which could be attributed to the deposit type.
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