SummaryImmune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens.Video Abstract

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SummaryCD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.

We report baseline results of a community-based, targeted, low-dose CT (LDCT) lung cancer screening pilot in deprived areas of Manchester. Ever smokers, aged 55-74 years, were invited to 'lung health checks' (LHCs) next to local shopping centres, with immediate access to LDCT for those at high risk (6-year risk ≥1.51%, PLCO calculator). 75% of attendees (n=1893/2541) were ranked in the lowest deprivation quintile; 56% were high risk and of 1384 individuals screened, 3% (95% CI 2.3% to 4.1%) had lung cancer (80% early stage) of whom 65% had surgical resection. Taking lung cancer screening into communities, with an LHC approach, is effective and engages populations in deprived areas.

Severe asthma is associated with the activation of circulating CD8(+) T cells but not CD4(+) T cells. This response is correlated with the downregulation of miR-146a/b and miR-28-5p, as well as changes in the expression of multiple species of lncRNA that might regulate CD8(+) T-cell function.

TRACERx, a prospective study of patients with primary non-small cell lung cancer, aims to map the genomic landscape of lung cancer by tracking clonal heterogeneity and tumour evolution from diagnosis to relapse.

The advent of techniques such as microarrays and high-throughput sequencing has revolutionized our ability to examine messenger RNA (mRNA) expression within the respiratory system. Importantly, these approaches have also uncovered the widespread expression of "noncoding RNAs," including microRNAs and long noncoding RNAs, which impact biologic responses through the regulation of mRNA transcription and/or translation. To date, most studies of the role of noncoding RNAs have focused on microRNAs, which regulate mRNA translation via the RNA interference pathway. These studies have shown changes in microRNA expression in cells and tissues derived from patients with asthma, pulmonary fibrosis, cystic fibrosis, COPD, and non-small cell lung cancer. Although the evidence is currently limited, we review the work that has been carried out in cell and animal models that has identified the function and mechanism of action of a small number of these microRNAs in disease etiology. In addition to microRNAs, we assess the emerging evidence that long noncoding RNAs regulate respiratory phenotype. Because these investigations into long noncoding RNAs were performed almost exclusively in non-small cell lung cancer, future work will need to extend these into other respiratory diseases and to analyze how microRNAs and long noncoding RNAs interact to regulate mRNA expression. From a clinical perspective, the targeting of noncoding RNAs as a novel therapeutic approach will require a deeper understanding of their function and mechanism of action. However, in the short term, changes in miRNA and long noncoding RNA expression are likely to be of use as biomarkers for disease stratification and/or assessment of drug action.

Flexible bronchoscopy is an essential, established and expanding tool in respiratory medicine. Its practice, however, needs to be safe, effective and for the right indications to maximise clinical utility. This guideline is based on the best available evidence and is a revised update of the British Thoracic Society guideline on diagnostic flexible bronchoscopy.Flexible bronchoscopy in adults is an essential, established and expanding tool in respiratory medicine. This new guideline aims to ensure that bronchoscopy remains a safe and effective procedure. Since the publication of the previous British Thoracic Society guideline on diagnostic flexible bronchoscopy in 2001 1 there has been a large amount of new evidence which has been incorporated into this guideline.