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- Ferreira, Alexandra Gabriela, et al.
(författare)
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Restoring tumor immunogenicity with dendritic cell reprogramming
- 2022
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Ingår i: Cancer immunology research. - 2326-6074. ; 10:12 suppl
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Konferensbidrag (refereegranskat)abstract
- Immunotherapy is revolutionizing cancer treatment, but success is limited to a fraction of patients. Tumor immunosurveillance and immunotherapy relies on presentation of tumor-associated antigens by conventional dendritic cells type 1 (cDC1). However, tumors develop mechanisms to avoid immune recognition such as downregulation of antigen presentation and exclusion of cDC1. We have previously demonstrated that enforced expression of the transcription factors PU.1, IRF8 and BATF3 (PIB) imposes the lineage conversion of fibroblasts to cDC1 by direct cell reprogramming. Here, we hypothesize that PIB reprograms cancer cells directly into functional tumor-antigen presenting cells (tumor-APCs) with enhanced immunogenicity. First, we show that enforced expression of PIB in a wide range of murine and human cancer cells from different origins is sufficient to induce surface expression of hematopoietic and DC-lineage specific markers (CD45 and Clec9a). Moreover, reprogramming restored the expression of antigen presentation complexes (MHC-I and MHC-II) and activated the expression of the co-stimulatory molecules CD40, CD80 and CD86, required for productive T cell activation. Transcriptomic analysis using mRNA-sequencing showed that PIB imposes a global cDC1 gene signature and an antigen presentation program in tumor cells as early as day 3 of reprogramming, overriding the original cancer cell program. Furthermore, Assay for Transposase-Accessible Chromatin (ATAC) sequencing analysis revealed that PIB-mediated cDC1 reprogramming elicited rapid epigenetic remodeling followed by gradual rewiring of transcriptional program and stabilization of cDC1 identity. Functionally, tumor-APCs present endogenous antigens on MHC-I, prime naïve CD8+ T and become prone to CD8+ T cell mediated killing. Tumor-APCs secrete pro-inflammatory cytokines (IL-12) and chemoattractants (CXCL10), uptake and process exogenous antigens, phagocyte dead cells, and cross-present exogenous antigens to activate naïve T-cells. In addition, reprogrammed tumor cells harboring TP53, KRAS and PTEN mutations downregulated proliferation and showed impaired tumorigenicity in vitro and in vivo. Importantly, we show that intra-tumoral injection of reprogrammed tumor-APCs elicited tumour growth control in vivo alongside increasing infiltration of CD8+ T and NK cells in B16-OVA tumors. Finally, we showed that our approach can be employed to convert primary cancer cells derived from melanoma, lung, breast, pancreatic, urothelial, and head and neck carcinomas as well as cancer associated fibroblasts. In summary, we provide evidence for the direct reprogramming of tumor cells into immunogenic cDC1-like cells, with restored antigen presentation capacity and the ability to reinstate anti-tumor immunity. Our approach elicits the immune system against cancer and counteract major tumor evasion mechanisms including tumor heterogeneity and impaired antigen presentation, laying the foundation for developing immunotherapeutic strategies based on the cellular reprogramming of human cancer cells.
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- Martijn, H., et al.
(författare)
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Development of IR imaging at IRnova
- 2009
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Ingår i: Infrared Technology and Applications XXXV. - : SPIE.
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Konferensbidrag (refereegranskat)abstract
- Historically IRnova has exclusively been a company, focused on manufacturing of QWIP detectors. Nowadays, besides continuous improvements of the performance of QWIP FPAs and development of new formats IRnova is involved in development of QWIP detectors for special applications and has started the development of the next generation infrared detectors, as well. In the light of the development of new formats we validate experimentally theoretical calculations of the response of QWIPs for smaller pixel size. These results allow for the development of high performance megapixel QWIP FPA that exhibit the high uniformity and operability QWIP detectors are known for. QWIP is also being considered for space applications. The requirements on dark current and operating temperature are however much more stringent as compared to the terrestrial applications. We show ways to improve the material quality with as a result a higher detector operating temperature. IRnova is also looking at antimony-based strained superlattice material for the LWIR region together with partners at theIMAGIC centre of excellence. One of the ways to overcome the problem with surface currents is passivating overgrowth. We will report the status and results of overgrowing the detector mesas with AlGa(As)Sb in a MOVPE system. At the same centre of excellence a novel material concept is being developed for LWIR detection. This new material contains a superlattice of vertically aligned and electronically coupled InAs and GaSb quantum dots. Simulations show that it should be possible to have LWIR detection in this material. We will present the current status and report results in this research.
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- Tofigh, Ali, et al.
(författare)
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A global structural em algorithm for a model of cancer progression
- 2011
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Ingår i: Adv. Neural Inf. Process. Syst.: Annu. Conf. Neural Inf. Process. Syst., NIPS. - : Neural Information Processing Systems.
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Konferensbidrag (refereegranskat)abstract
- Cancer has complex patterns of progression that include converging as well as diverging progressional pathways. Vogelstein's path model of colon cancer was a pioneering contribution to cancer research. Since then, several attempts have been made at obtaining mathematical models of cancer progression, devising learning algorithms, and applying these to cross-sectional data. Beerenwinkel et al. provided, what they coined, EM-like algorithms for Oncogenetic Trees (OTs) and mixtures of such. Given the small size of current and future data sets, it is important to minimize the number of parameters of a model. For this reason, we too focus on tree-based models and introduce Hidden-variable Oncogenetic Trees (HOTs). In contrast to OTs, HOTs allow for errors in the data and thereby provide more realistic modeling. We also design global structural EM algorithms for learning HOTs and mixtures of HOTs (HOT-mixtures). The algorithms are global in the sense that, during the M-step, they find a structure that yields a global maximum of the expected complete log-likelihood rather than merely one that improves it. The algorithm for single HOTs performs very well on reasonable-sized data sets, while that for HOT-mixtures requires data sets of sizes obtainable only with tomorrow's more cost-efficient technologies.
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- Wang, Q., et al.
(författare)
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Multilayer InAs/InGaAs quantum dot structure grown by MOVPE for optoelectronic device applications
- 2006
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Ingår i: Nanoengineering: Fabrication, Properties, Optics, and Devices III. - : SPIE. ; , s. L3270-L3270
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Konferensbidrag (refereegranskat)abstract
- We report on a quantum dot (QD) structure grown on a 4" GaAs substrate by metal organic vapor phase epitaxy (MOVPE), which consists of five stacked InAs/InGaAs/GaAs QD layers embedded in the center of a typical in-plane waveguide. The density of the QDs is about 2.5 × 1010 cm -2 per QD layer. The photoluminescence (PL) peak wavelength at 1322 nm corresponding to the interband transition of the QD ground states was observed at room temperature with a full width at half-maximum of 49 meV. A good uniformity of the QD structure across the 4" wafer was verified with a variation of the PL peak wavelength of 0.9 % from the wafer center to the edge. Top p-contacts and a bottom n-contact were processed on the QD structure, and electroluminescence (EL) spectra were measured at different temperatures. An EL peak corresponding to the QD ground states emission was obtained at 1325 nm at room temperature.
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