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.

Background Over half a million individuals are diagnosed with head and neck cancer each year globally. Radiotherapy is an important curative treatment for this disease, but it requires manual time to delineate radiosensitive organs at risk. This planning process can delay treatment while also introducing interoperator variability, resulting in downstream radiation dose differences. Although auto-segmentation algorithms offer a potentially time-saving solution, the challenges in defining, quantifying, and achieving expert performance remain. Objective Adopting a deep learning approach, we aim to demonstrate a 3D U-Net architecture that achieves expert-level performance in delineating 21 distinct head and neck organs at risk commonly segmented in clinical practice. Methods The model was trained on a data set of 663 deidentified computed tomography scans acquired in routine clinical practice and with both segmentations taken from clinical practice and segmentations created by experienced radiographers as part of this research, all in accordance with consensus organ at risk definitions. Results We demonstrated the model’s clinical applicability by assessing its performance on a test set of 21 computed tomography scans from clinical practice, each with 21 organs at risk segmented by 2 independent experts. We also introduced surface Dice similarity coefficient, a new metric for the comparison of organ delineation, to quantify the deviation between organ at risk surface contours rather than volumes, better reflecting the clinical task of correcting errors in automated organ segmentations. The model’s generalizability was then demonstrated on 2 distinct open-source data sets, reflecting different centers and countries to model training. Conclusions Deep learning is an effective and clinically applicable technique for the segmentation of the head and neck anatomy for radiotherapy. With appropriate validation studies and regulatory approvals, this system could improve the efficiency, consistency, and safety of radiotherapy pathways.

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