IMPROVE: a feature model to predict neoepitope immunogenicity through broad-scale validation of T-cell recognition.

Background: Mutation-derived neoantigens are critical targets for tumor rejection in cancer immunotherapy, and better tools for neoepitope identification and prediction are needed to improve neoepitope targeting strategies. Computational tools have enabled the identification of patient-specific neoantigen candidates from sequencing data, but limited data availability has hindered their capacity to predict which of the many neoepitopes will most likely give rise to T cell recognition.

Method: To address this, we make use of experimentally validated T cell recognition towards 17,500 neoepitope candidates, with 467 being T cell recognized, across 70 cancer patients undergoing immunotherapy.

A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo.

Acute myeloid leukemia (AML), the most frequent leukemia in adults, is driven by recurrent somatically acquired genetic lesions in a restricted number of genes. Treatment with tyrosine kinase inhibitors has demonstrated that targeting of prevalent FMS-related receptor tyrosine kinase 3 (FLT3) gain-of-function mutations can provide significant survival benefits for patients, although the efficacy of FLT3 inhibitors in eliminating FLT3-mutated clones is variable. We identified a T cell receptor (TCR) reactive to the recurrent D835Y driver mutation in the FLT3 tyrosine kinase domain (TCR).

Fundamental immune-oncogenicity trade-offs define driver mutation fitness.

Missense driver mutations in cancer are concentrated in a few hotspots. Various mechanisms have been proposed to explain this skew, including biased mutational processes, phenotypic differences and immunoediting of neoantigens; however, to our knowledge, no existing model weighs the relative contribution of these features to tumour evolution. We propose a unified theoretical 'free fitness' framework that parsimoniously integrates multimodal genomic, epigenetic, transcriptomic and proteomic data into a biophysical model of the rate-limiting processes underlying the fitness advantage conferred on cancer cells by driver gene mutations.

Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma.

CD8 T cell reactivity towards tumor mutation-derived neoantigens is widely believed to facilitate the antitumor immunity induced by immune checkpoint blockade (ICB). Here we show that broadening in the number of neoantigen-reactive CD8 T cell (NART) populations between pre-treatment to 3-weeks post-treatment distinguishes patients with controlled disease compared to patients with progressive disease in metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. The longitudinal analysis of peripheral CD8 T cell recognition of patient-specific neopeptide libraries consisting of DNA barcode-labelled pMHC multimers in a cohort of 24 patients from the clinical trial NCT02108652 also shows that peripheral NARTs derived from patients with disease control are characterised by a PD1 Ki67 effector phenotype and increased CD39 levels compared to bystander bulk- and virus-antigen reactive CD8 T cells.

Tracking evolution of myoglobin stability in cetaceans using experimentally calibrated computational methods that account for generic protein relaxation.

The evolution of cetaceans (whales, dolphins, and porpoises) from land to water is one of the most spectacular events in mammal evolution. It has been suggested that selection for higher myoglobin stability (∆G of folding) allowed whales to conquer the deep-diving niche. The stability of multi-site protein variants, including ancient proteins, is however hard to describe theoretically.

Polarity-Driven Quasi-3-Fold Composition Symmetry of Self-Catalyzed III-V-V Ternary Core-Shell Nanowires.

A quasi-3-fold composition symmetry has for the first time been observed in self-catalyzed III-V-V core-shell nanowires. In GaAsP nanowires, phosphorus-rich sheets on radial {110} planes originating at the corners of the hexagonal core were observed. In a cross section, they appear as six radial P-rich bands that originate at the six outer corners of the hexagonal core, with three of them higher in P content along ⟨112⟩A direction and others along ⟨112⟩B, forming a quasi-3-fold composition symmetry.

Self-catalyzed ternary core-shell GaAsP nanowire arrays grown on patterned Si substrates by molecular beam epitaxy.

The growth of self-catalyzed ternary core-shell GaAsP nanowire (NW) arrays on SiO2 patterned Si(111) substrates has been demonstrated by using solid-source molecular beam epitaxy. A high-temperature deoxidization step up to ∼ 900 °C prior to NW growth was used to remove the native oxide and/or SiO2 residue from the patterned holes. To initiate the growth of GaAsP NW arrays, the Ga predeposition used for assisting the formation of Ga droplets in the patterned holes, was shown to be another essential step.

A step closer to membrane protein multiplexed nanoarrays using biotin-doped polypyrrole.

Whether for fundamental biological research or for diagnostic and drug discovery applications, protein micro- and nanoarrays are attractive technologies because of their low sample consumption, high-throughput, and multiplexing capabilities. However, the arraying platforms developed so far are still not able to handle membrane proteins, and specific methods to selectively immobilize these hydrophobic and fragile molecules are needed to understand their function and structural complexity. Here we integrate two technologies, electropolymerization and amphipols, to demonstrate the electrically addressable functionalization of micro- and nanosurfaces with membrane proteins.

Self-catalyzed GaAsP nanowires grown on silicon substrates by solid-source molecular beam epitaxy.

We realize the growth of self-catalyzed GaAsP nanowires (NWs) on silicon (111) substrates using solid-source molecular beam epitaxy. By optimizing the V/III and P/As flux ratios, as well as the Ga flux, high-crystal-quality GaAsP NWs have been demonstrated with almost pure zinc-blende phase. Comparing the growth of GaAsP NWs with that of the conventional GaAs NWs indicates that the incorporation of P has significant effects on catalyst nucleation energy, and hence the nanowire morphology and crystal quality.

Surface-passivated GaAsP single-nanowire solar cells exceeding 10% efficiency grown on silicon.

Continued development of high-efficiency multi-junction solar cells requires growth of lattice-mismatched materials. Today, the need for lattice matching both restricts the bandgap combinations available for multi-junctions solar cells and prohibits monolithic integration of high-efficiency III-V materials with low-cost silicon solar cells. The use of III-V nanowires is the only known method for circumventing this lattice-matching constraint, and therefore it is necessary to develop growth of nanowires with bandgaps >1.