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

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.

Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. (Funded by Becton Dickinson; EudraCT number, 2012-000599-40 .).

Background: With the release of the National Lung Screening Trial results, the detection of peripheral pulmonary lesions (PPLs) is likely to increase. Computed tomography (CT)-guided percutaneous transthoracic needle biopsy (PTNB) and radial probe endobronchial ultrasound (r-EBUS)-guided transbronchial lung biopsy (TBLB) are recommended for tissue diagnosis of PPLs.Methods: A systematic review of published literature evaluating the accuracy of r-EBUS-TBLB and CT-PTNB for the diagnosis of PPLs was performed to determine point sensitivity and specificity, and to construct a summary receiver-operating characteristic curve.Results: This review included 31 publications dealing with EBUS-TBLB and 14 publications dealing with CT-PTNB for the diagnosis of PPLs. EBUS-TBLB had point sensitivity of 0.69 (95% CI: 0.67-0.71) for the diagnosis of peripheral lung cancer (PLC), which was lower than the sensitivity of CT-PTNB (0.94, 95% CI: 0.94-0.95). However, the complication rates observed with EBUS-TBLB were lower than those reported for CT-PTNB.Conclusions: This meta-analysis showed that EBUS-TBLB is a safe and relatively accurate tool in the investigation of PLC. Although the yield remains lower than that of CT-PTNB, the procedural risks are lower.Keywords: Computed tomography-guided percutaneous transthoracic needle biopsy (CT-PTNB); radial probe endobronchial ultrasound-guided transbronchial lung biopsy (r-EBUS-TBLB); peripheral pulmonary lesions; diagnosis; meta-analysis

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