Clonality of CD4+ Blood T Cells Predicts Longer Survival With CTLA4 or PD-1 Checkpoint Inhibition in Advanced Melanoma

Recognition of cancer antigens drives the clonal expansion of cancer-reactive T cells, which is thought to contribute to restricted T-cell receptor (TCR) repertoires in tumor-infiltrating lymphocytes (TILs). To understand how tumors escape anti-tumor immunity, we investigated tumor-associated T-cell repertoires of patients with advanced melanoma and after blockade of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD-1). TCR Vβ-gene spectratyping allowed us to quantify restrictions of T-cell repertoires and, further, diversities of T-cell clones. In this study, we show that the blood TCR repertoires were variably restricted in CD4+ and extensively restricted in CD8+ T cells of patients with advanced melanoma, and contained clones in both T-cell fractions prior to the start of immunotherapy. A greater diversification especially of CD4+ blood T-cell clones before immunotherapy showed statistically significant correlations with long-term survival upon CTLA4 or PD-1 inhibition. Analysis of TILs and corresponding blood available in one patient indicated that blood clonality may at least partially be related to the clonal expansion in the tumor microenvironment. In patients who developed severe immune-related adverse events (IrAEs), CD4+ and CD8+ TCR spectratypes became more restricted during anti-CTLA4 treatment, suggesting that newly expanded oligoclonal T-cell responses may contribute to IrAEs. This study reveals diverse T-cell clones in the blood of melanoma patients prior to immunotherapy, which may reflect the extent to which T cells are able to react against melanoma and potentially control melanoma progression. Therefore, the T-cell clonality in the circulation may have predictive value for antitumor responses from checkpoint inhibition

Fabry-Perot interference and spin filtering in carbon nanotubes

We study the two-terminal transport properties of a metallic single-walled carbon nanotube with good contacts to electrodes, which have recently been shown [W. Liang et al, Nature 441, 665-669 (2001)] to conduct ballistically with weak backscattering occurring mainly at the two contacts. The measured conductance, as a function of bias and gate voltages, shows an oscillating pattern of quantum interference. We show how such patterns can be understood and calculated, taking into account Luttinger liquid effects resulting from strong Coulomb interactions in the nanotube. We treat back-scattering in the contacts perturbatively and use the Keldysh formalism to treat non-equilibrium effects due to the non-zero bias voltage. Going beyond current experiments, we include the effects of possible ferromagnetic polarization of the leads to describe spin transport in carbon nanotubes. We thereby describe both incoherent spin injection and coherent resonant spin transport between the two leads. Spin currents can be produced in both ways, but only the latter allow this spin current to be controlled using an external gate. In all cases, the spin currents, charge currents, and magnetization of the nanotube exhibit components varying quasiperiodically with bias voltage, approximately as a superposition of periodic interference oscillations of spin- and charge-carrying ``quasiparticles'' in the nanotube, each with its own period. The amplitude of the higher-period signal is largest in single-mode quantum wires, and is somewhat suppressed in metallic nanotubes due to their sub-band degeneracy.Comment: 12 pages, 6 figure

Habitat properties are key drivers of Borrelia burgdorferi (s.l.) prevalence in Ixodes ricinus populations of deciduous forest fragments

Background: The tick Ixodes ricinus has considerable impact on the health of humans and other terrestrial animals because it transmits several tick-borne pathogens (TBPs) such as B. burgdorferi (sensu lato), which causes Lyme borreliosis (LB). Small forest patches of agricultural landscapes provide many ecosystem services and also the disservice of LB risk. Biotic interactions and environmental filtering shape tick host communities distinctively between specific regions of Europe, which makes evaluating the dilution effect hypothesis and its influence across various scales challenging. Latitude, macroclimate, landscape and habitat properties drive both hosts and ticks and are comparable metrics across Europe. Therefore, we instead assess these environmental drivers as indicators and determine their respective roles for the prevalence of B. burgdorferi in I. ricinus. Methods: We sampled I. ricinus and measured environmental properties of macroclimate, landscape and habitat quality of forest patches in agricultural landscapes along a European macroclimatic gradient. We used linear mixed models to determine significant drivers and their relative importance for nymphal and adult B. burgdorferi prevalence. We suggest a new prevalence index, which is pool-size independent. Results: During summer months, our prevalence index varied between 0 and 0.4 per forest patch, indicating a low to moderate disservice. Habitat properties exerted a fourfold larger influence on B. burgdorferi prevalence than macroclimate and landscape properties combined. Increasingly available ecotone habitat of focal forest patches diluted and edge density at landscape scale amplified B. burgdorferi prevalence. Indicators of habitat attractiveness for tick hosts (food resources and shelter) were the most important predictors within habitat patches. More diverse and abundant macro- and microhabitat had a diluting effect, as it presumably diversifies the niches for tick-hosts and decreases the probability of contact between ticks and their hosts and hence the transmission likelihood.[br/] Conclusions: Diluting effects of more diverse habitat patches would pose another reason to maintain or restore high biodiversity in forest patches of rural landscapes. We suggest classifying habitat patches by their regulating services as dilution and amplification habitat, which predominantly either decrease or increase B. burgdorferi prevalence at local and landscape scale and hence LB risk. Particular emphasis on promoting LB-diluting properties should be put on the management of those habitats that are frequently used by humans. In the light of these findings, climate change may be of little concern for LB risk at local scales, but this should be evaluated further

Autoimmune aspects of psoriasis: Heritability and autoantigens

Chronic immune-mediated disorders (IMDs) constitute a major health burden. Understanding IMD pathogenesis is facing two major constraints: Missing heritability explaining familial clustering, and missing autoantigens. Pinpointing IMD risk genes and autoimmune targets, however, is of fundamental importance for developing novel causal therapies. The strongest association of all IMDs is seen with human leukocyte antigen (HLA) alleles. Using psoriasis as an IMD model this article reviews the pathogenic role HLA molecules may have within the polygenic predisposition of IMDs. It concludes that disease-associated HLA alleles account for both missing heritability and autoimmune mechanisms by facilitating tissue-specific autoimmune responses through autoantigen presentation. (C) 2017 The Author. Published by Elsevier B.V

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Practical guidance on immunogenicity to biologic agents used in the treatment of psoriasis: what can be learnt from other diseases?

The clinical efficacy of biologic agents for the treatment of moderate to severe psoriasis is well proven in clinical studies, but patients may lose response over time. Loss of response may be due to immunogenicity and the formation of anti-drug antibodies (ADA). Although data on the immunogenicity of drugs used to treat psoriasis are now emerging, more information on the impact of factors, such as dosing regimens and concomitant immunosuppressive therapy is needed. Exploring research from other disease areas where immunogenicity has long been recognised as a significant clinical issue may help in developing future strategies for using drug level and ADA measurements to help tailor biologic therapy to meet individual needs. To this end, we analyse what is known about biologics and immunogenicity in psoriasis. In order to learn from other indications, we then address the issue of immunogenicity for three different types of biologic treatments. First, factor VIII-substitution in haemophilia, where the immune system is newly exposed to a physiologic but formerly absent protein. Second, the use of biologics in inflammatory bowel disease, where similar treatment challenges apply as observed in psoriasis. Third, immunogenicity in multiple sclerosis caused by therapeutic antibodies or interferons. Immunogenicity strategies used in other disease areas will need to be tested in psoriasis before they can be widely adopted in routine clinical practice