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.

Vulnerability to MDD is associated with temporofrontolimbic decoupling that is selective for self-blaming feelings. This provides the first neural mechanism ofMDD vulnerability that accounts for self-blaming biases.

The Cretaceous/Palaeogene mass extinction eradicated 76% of species on Earth. It was caused by the impact of an asteroid on the Yucatán carbonate platform in the southern Gulf of Mexico 66 million years ago , forming the Chicxulub impact crater. After the mass extinction, the recovery of the global marine ecosystem-measured as primary productivity-was geographically heterogeneous ; export production in the Gulf of Mexico and North Atlantic-western Tethys was slower than in most other regions, taking 300 thousand years (kyr) to return to levels similar to those of the Late Cretaceous period. Delayed recovery of marine productivity closer to the crater implies an impact-related environmental control, such as toxic metal poisoning , on recovery times. If no such geographic pattern exists, the best explanation for the observed heterogeneity is a combination of ecological factors-trophic interactions , species incumbency and competitive exclusion by opportunists -and 'chance'. The question of whether the post-impact recovery of marine productivity was delayed closer to the crater has a bearing on the predictability of future patterns of recovery in anthropogenically perturbed ecosystems. If there is a relationship between the distance from the impact and the recovery of marine productivity, we would expect recovery rates to be slowest in the crater itself. Here we present a record of foraminifera, calcareous nannoplankton, trace fossils and elemental abundance data from within the Chicxulub crater, dated to approximately the first 200 kyr of the Palaeocene. We show that life reappeared in the basin just years after the impact and a high-productivity ecosystem was established within 30 kyr, which indicates that proximity to the impact did not delay recovery and that there was therefore no impact-related environmental control on recovery. Ecological processes probably controlled the recovery of productivity after the Cretaceous/Palaeogene mass extinction and are therefore likely to be important for the response of the ocean ecosystem to other rapid extinction events.

IMPORTANCE Patients with remitted major depressive disorder (MDD) were previously found to display abnormal functional magnetic resonance imaging connectivity (fMRI) between the right superior anterior temporal lobe (RSATL) and the subgenual cingulate cortex and adjacent septal region (SCSR) when experiencing self-blaming emotions relative to emotions related to blaming others (eg, "indignation or anger toward others"). This finding provided the first neural signature of biases toward overgeneralized self-blaming emotions (eg, "feeling guilty for everything"), known to have a key role in cognitive vulnerability to MDD. It is unknown whether this neural signature predicts risk of recurrence, a crucial step in establishing its potential as a prognostic biomarker, which is urgently needed for stratification into pathophysiologically more homogeneous subgroups and for novel treatments. OBJECTIVE To use fMRI in remitted MDD at baseline to test the hypothesis that RSATL-SCSR connectivity for self-blaming relative to other-blaming emotions predicts subsequent recurrence of depressive episodes. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study from June 16, 2011, to October 10, 2014, in a clinical research facility completed by 75 psychotropic medication-free patients with remitted MDD and no relevant comorbidity. In total, 31 remained in stable remission, and 25 developed a recurring episode over the 14 months of clinical follow-up and were included in the primary analysis. Thirty-nine control participants with no personal or family history of MDD were recruited for further comparison. MAIN OUTCOMES AND MEASURES Between-group difference (recurring vs stable MDD) in RSATL connectivity, with an a priori SCSR region of interest for self-blaming vs other-blaming emotions. RESULTS We corroborated our hypothesis that during the experience of self-blaming vs other-blaming emotions, RSATL-SCSR connectivity predicted risk of subsequent recurrence. The recurring MDD group showed higher connectivity than the stable MDD group (familywise error-corrected P < .05 over the a priori SCSR region of interest) and the control group. In addition, the recurring MDD group also exhibited RSATL hyperconnectivity with the right ventral putamen and claustrum and the temporoparietal junction. Together, these regions predicted recurrence with 75% accuracy. CONCLUSIONS AND RELEVANCE To our knowledge, this study is the first to provide a robust demonstration of an fMRI signature of recurrence risk in remitted MDD. Additional studies are needed for its further optimization and validation as a prognostic biomarker.