198 research outputs found
Development of next-generation immunomodulatory antibodies for cancer therapy through optimization of the IgG framework
No full textIn this issue of Cancer Cell, Dahan and colleagues demonstrate that the Fc region has a significant impact on the therapeutic capacity of checkpoint inhibitor antibodies targeting the PD-1/PD-L1 axis in pre-clinical tumor models. This work provides important insights with respect to the further clinical development of checkpoint inhibitors
Radiation-induced alterations in immunogenicity of a murine pancreatic ductal adenocarcinoma cell line
No full textPancreatic ductal adenocarcinoma (PDA) is highlighted by resistance to radiotherapy with the possible exception of hypofractionated irradiation. As single photon doses were reported to increase immunogenicity, we investigated dose-dependent irradiation effects on clonogenic survival, expression of immunologically relevant cell surface molecules and susceptibility to cytotoxic T cell (CTL) mediated killing using a murine PDA cell line. Clonogenicity decreased in a dose-responsive manner showing enhanced radioresistance at single photon doses below 5 Gy. Cell cycle analysis revealed a predominant G2/M arrest, being most pronounced 12 h after irradiation. Polyploidy increased in a dose- and time-dependent manner reaching a maximum frequency 60 h following irradiation with 10 Gy. Irradiation increased surface expression of MHC class I molecules and of immunological checkpoint molecules PDL-1 and CD73, especially at doses ≥ 5 Gy, but not of MHC class II molecules and CXCR4 receptors. Cytotoxicity assays revealed increased CTL lysis of PDA cells at doses ≥ 5 Gy. For the PDA cell line investigated, our data show for the first time that single photon doses ≥ 5 Gy effectively inhibit colony formation and induce a G2/M cell cycle arrest. Furthermore, expression levels of immunomodulatory cell surface molecules became altered possibly enhancing the susceptibility of tumour cells to CTL lysis
Exploring potential human cancer neoantigens as targets for adoptive T cell therapy
No full textDer adoptive Transfer von T-Zell-Rezeptor (TZR) modifizierten T-Zellen gegen krebsspezifische Antigene ist ein vielversprechender Ansatz in der Immuntherapie. Geeignete Zielmoleküle für diese Therapie sollten wichtig für das Überleben von Krebszellen sein und zudem in ausreichenden Mengen auf der Zelloberfläche exprimiert werden, um von T-Zellen erkannt zu werden. Die Identifizierung dieser Zielmoleküle ist jedoch eine Herausforderung und erfordert eine intensive Charakterisierung, um eine ausreichende Prozessierung und Präsentation auf den Tumorzellen zu validieren.
Ziel dieser Arbeit war, HLA-A2-spezifische Neoepitope als Zielmoleküle für adoptive T-Zell-Therapie zu validieren. Dafür wurden erfolgreich Immunantworten in einem humanen transgenen Mausmodell nach Peptidimmunisierung induziert und TZRs mit hoher Affinität isoliert. Trotz einer hohen funktionellen Avidität von H3.3K27M-spezifischen T-Zellen wurde keine Erkennung von Tumorzellen erreicht. Zweitens wurden TZR-transduzierte T-Zellen gegen die häufige Melanommutation Rac1P29S isoliert, welche zytotoxisch gegen Melanomzelllinien waren. Letztlich wurde beobachtetet, dass TZRs mit hoher Affinität gegen gespleißte Kras und Rac2 Epitope, welche durch Proteasom-katalysiertes Peptidspleißen erzeugt wurden, keine Immunantwort gegen endogen exprimierte Mutationen hervorrufen konnten. Daraus lässt sich schließen, dass gespleißte Epitope wahrscheinlich seltener vorkommen als zuvor angenommen und daher möglicherweise irrelevant für die adoptive T-Zelltherapie sind.
Diese Daten deuten darauf hin, dass die Auswahl von Zielmolekülen für die adoptive T-Zell-Therapie mit Hilfe reverser Immunologie auf der Grundlage von Bindungsalgorithmen und der Häufigkeit von Mutationen allein nicht ausreicht. Daher sind vor der Isolierung und Charakterisierung von TZRs zusätzliche Strategien wie z.B. die Analyse des MHC-Immunopeptidoms erforderlich, um die Auswahl geeigneter Zielmoleküle für die T-Zelltherapie zu verbessern.Adoptive transfer of T cell receptor (TCR)-engineered T cells against tumour-specific neoantigens is a promising approach in cancer immunotherapy. Ideally, targeted antigens are crucial for cancer cell survival and are generated in sufficient amounts to be recognised by T cells. However, the identification of ideal targets remains challenging and requires intensive characterisation to validate sufficient antigen processing and presentation by the tumour cells.
This thesis focused on the validation of HLA-A2 binding neoepitopes carrying the recurrent cancer mutations H3.3K27M, Rac1P29S, Rac2P29L or KrasG12V as targets for adoptive T cell therapy. After peptide immunisation, immune responses in a human transgenic mouse model were elicited and high-affinity TCRs successfully isolated. Although H3.3K27M-specific T cells showed high functional avidity, no recognition of cells endogenously expressing mutant H3.3 was achieved. Furthermore, a mechanism to target the common melanoma mutation Rac1P29S with a TCR raised against a heterologous mutation with higher peptide-MHC affinity was described. TCR-transduced T cells induced cytotoxicity against Rac1P29S expressing melanoma cell lines. Lastly, high-affinity TCRs specific for mutant Kras and Rac2 spliced epitopes generated by proteasome-catalysed peptide splicing were successfully isolated, however, TCR-transduced T cells did not induce an immune response against endogenously expressed mutant transgenes. The results indicate that spliced epitopes are probably less abundant than previously estimated and therefore may play a minor role in the generation of targets for adoptive T cell therapy.
These data suggest that target selection using a reverse immunology approach based on binding algorithms and frequency of mutations alone is not sufficient. Thus, additional strategies to improve the selection of suitable targets such as the analysis of the MHC immunopeptidome are required prior to TCR isolation and characterisation
Oligodonta florissantensis
No full textflorissantensis. Oligodonta florissantensis Brown, 1976 Fig. 8. Nymphalidae: Libytheinae. USA, Colorado, Florissant; late Priabonian, late Eocene. Depository: FFNM (holotype). Published figures: Brown (1976: Figs 1–3); Emmel et al. (1992: Fig. 1 /2, and at back of color plate III); Kawahara (2013: Fig. 62). For a good description and interpretation of the fossil, see Kawahara (2013).This author synonymized it with Barbarothea florissanti (see below) and placed it in the extant genus Libytheana (Nymphalidae), see description below. It was placed in the Pieridae by Brown (1976) (followed by Emmel et al. 1992), because of the unjustly supposed similarity with Leodonta. Subsequently, Braby et al. (2006) used the fossil as calibration point on the phylogenetic tree of the Pieridae as a close relative of the Catasticta group, if not the genus Leodonta.Published as part of Jong, Rienk De, 2017, Fossil butterflies, calibration points and the molecular clock (Lepidoptera: Papilionoidea), pp. 1-63 in Zootaxa 4270 (1) on page 26, DOI: 10.5281/zenodo.58318
Prodryas persephone
No full textpersephone. Prodryas persephone Scudder, 1878 Nymphalidae. USA, Colorado, Teller County, Florissant; late Priabonian, late Eocene. Depository: MCZH (holotype, no. 394). Published figure: Emmel et al. (1992: Fig. 1 /5, and at back of color plate III); Murata (1998: Figs 46–49); Scudder (1889: Pl. LII Figs. 1 –10). After the original decription (Scudder 1878), the author described and figured this specimen extensively in 1889. A well preserved, medium-sized (length of forewing 24.5 mm) and strongly built insect. The forewing, radial formula is 1, 2+(3+(4+5)), udc originates between R1 and R2 (slightly closer to R1); M1 and M2 originate close together near upper cell corner; cell open. In the hindwing Rs originates far basad; cell open; tail at M3, from here to tornus termen crenulate. The open cell in forewing and hindwing is an apomorphy found in many Nymphalinae and separately derived in some members of other nymphalid subfamilies. Emmel et al. (1992) assigned the fossil to this subfamily, but in the absence of additional apomorphies, we cannot be sure about the subfamily. On the basis of overall similarity with extant genera, earlier authors have discussed its identification. According to Forbes (1932) and Brown (1978) the fossil is very close to the modern genus Hypanartia. This genus occurs, with eight species, in Central and South America (DeVries 1987). This author thought this fossil was a close relative of the African genus Antanartia (see also Brown & Heineman 1972), but Wahlberg et al. (2009) place Hypanartia as sister to Vanessa, and Antanartia as sister to Aglais, Polygonia, Nymphalis and Kaniska. One species of Hypanartia may occasionally stray into the southern USA (Scott 1986). Wahlberg et al. (2005a, 2009) and Heikkilä et al. (2011) followed Forbes and Brown in additionn to personal information from Willmot that the fossil is very close to Hypanartia and used the fossil as calibration point for the split between Vanessa and Hypanartia. This is an undesirable situation, since any information on characters, let alone apomorphies, is missing. Brown's (1978: 8) remark: "Careful examination of Scudder's type has led to the realization that it is little different, if any, from the modern genus Hypanartia." sounds reassuring, but does not convey much information on the presence of apomorphic characters. It is reminiscent of the case of Vanessa amerindica (see above), which is considered a member of the genus Vanessa because of the presence of a produced forewing apex with a lobe at M1- M2, a character that does not seem to be restricted to this genus. It must be remarked that the double spot between M2 and M3, clearly indicated in Scudder’s figures, is unlike any feature found in recent butterflies. If there is a spot in this space, it is always single, and if there is a spot between M1 and M2, it is close to the spot between M2 and M3 and not placed further basad. It seems possible that the division of the spot between M2 and M 3 in the fossil is an artefact.Published as part of Jong, Rienk De, 2017, Fossil butterflies, calibration points and the molecular clock (Lepidoptera: Papilionoidea), pp. 1-63 in Zootaxa 4270 (1) on page 34, DOI: 10.5281/zenodo.58318
Next-generation TCR sequencing - a tool to understand T-cell infiltration in human cancers.
No full textTumour-infiltrating lymphocytes (TILs) are known to mediate potent anti-tumour activity. As T-cell-based therapies start to reach clinical practice, it becomes increasingly important to understand what characterizes a successful anti-tumour T-cell response and to exploit this knowledge for patient stratification. Next-generation sequencing of T-cell receptors (TCRs) promises to provide insights into the complexity of the tumour T-cell infiltrate that go beyond the phenotypic level. A recent study by Chen et al made use of this novel technology to demonstrate that the TIL repertoire of oesophageal squamous cell carcinoma patients is distinct from that of non-tumour sites and is characterized by significant intratumoural heterogeneity. This study illustrates the great potential of the method and addresses several technical and biological hurdles that need to be considered. Careful sampling, normalization, and error correction will be required to optimally use TCR sequencing to answer biological questions and define predictive biomarkers, e.g. for cancer immunotherapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
Wood-LOM: Using laminated object manufacturing to reimagine the use of wood
No full textThis study investigates the feasibility of manufacturing wooden elements using Layer Object Manufacturing (LOM) technology to replace steel nodes in the built environment. LOM offers significant advantages in allowing the designer to dictate the grain direction of each layer of material and optimize the cutting process, potentially reducing the amount of waste material produced. However, the technique is still in its developmental phase, and there is a lack of information available regarding its performance when used with wood. The study identifies design parameters for constructing solid wooden connection elements using LOM, including object geometry, grain direction, and layer segmentation. Wooden pegs are suggested to create reliable connections between a wood-LOM produced node and a timber structure.Architecture, Urbanism and Building Sciences | Building Technolog
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