Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer

Claudin-low breast cancer is an aggressive subtype that confers poor prognosis and is found largely within the clinical triple-negative group of breast cancer patients. Here, we have shown that intrinsic and immune cell gene signatures distinguish the claudin-low subtype clinically as well as in mouse models of other breast cancer subtypes. Despite adaptive immune cell infiltration in claudin-low tumors, treatment with immune checkpoint inhibitory antibodies against cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed death receptor 1 (PD-1) were ineffective in controlling tumor growth. CD4+FoxP3+ Tregs represented a large proportion of the tumor-infiltrating lymphocytes (TILs) in claudin-low tumors, and Tregs isolated from tumor-bearing mice were able to suppress effector T cell responses. Tregs in the tumor microenvironment highly expressed PD-1 and were recruited partly through tumor generation of the chemokine CXCL12. Antitumor efficacy required stringent Treg depletion combined with checkpoint inhibition; delays in tumor growth were not observed using therapies that modestly diminished the number of Tregs in the tumor microenvironment. This study provides evidence that the recruitment of Tregs to the tumor microenvironment inhibits an effective antitumor immune response and highlights early Treg recruitment as a possible mechanism for the lack of response to immune checkpoint blockade antibodies in specific subtypes of cancer that are heavily infiltrated with adaptive immune cells

Effective alcohol policies and lifetime abstinence An analysis of the International Alcohol Control policy index

Introduction Alcohol abstinence remains common among adults globally, although low and middle-income countries are experiencing declines in abstention. The effect of alcohol policies on lifetime abstinence is poorly understood. The International Alcohol Control (IAC) policy index was developed to benchmark and monitor the uptake of effective alcohol policies and has shown strong associations with alcohol per capita consumption and drinking patterns. Uniquely, the index incorporates both policy ‘stringency’ and ‘impact’, reflecting policy implementation and enforcement, across effective policies. Here we assessed the association of the IAC policy index with lifetime abstinence in a diverse sample of jurisdictions. Methods We conducted a cross-sectional analysis of the relationship between the IAC policy index score, and its components, and lifetime abstinence among adults (15+ years) in 13 high and middle-income jurisdictions. We examined the correlations for each component of the index and stringency and impact separately. Results Overall, the total IAC policy index scores were positively correlated with lifetime abstinence (r = 0.76), as were both the stringency (r = 0.62) and impact (r = 0.82) scores. Marketing restrictions showed higher correlations with lifetime abstinence than other policy domains (r = 0.80), including restrictions on physical availability, pricing policies and drink-driving prevention. Discussion and Conclusion Our findings suggest that restricting alcohol marketing could be an important policy for the protection of alcohol abstention. The IAC policy index may be a useful tool to benchmark the performance of alcohol policy in supporting alcohol abstention in high and middle-income countries.Output Status: Forthcoming/Available Onlin

Effective alcohol policies and lifetime abstinence An analysis of the International Alcohol Control policy index

Introduction Alcohol abstinence remains common among adults globally, although low and middle-income countries are experiencing declines in abstention. The effect of alcohol policies on lifetime abstinence is poorly understood. The International Alcohol Control (IAC) policy index was developed to benchmark and monitor the uptake of effective alcohol policies and has shown strong associations with alcohol per capita consumption and drinking patterns. Uniquely, the index incorporates both policy ‘stringency’ and ‘impact’, reflecting policy implementation and enforcement, across effective policies. Here we assessed the association of the IAC policy index with lifetime abstinence in a diverse sample of jurisdictions. Methods We conducted a cross-sectional analysis of the relationship between the IAC policy index score, and its components, and lifetime abstinence among adults (15+ years) in 13 high and middle-income jurisdictions. We examined the correlations for each component of the index and stringency and impact separately. Results Overall, the total IAC policy index scores were positively correlated with lifetime abstinence (r = 0.76), as were both the stringency (r = 0.62) and impact (r = 0.82) scores. Marketing restrictions showed higher correlations with lifetime abstinence than other policy domains (r = 0.80), including restrictions on physical availability, pricing policies and drink-driving prevention. Discussion and Conclusion Our findings suggest that restricting alcohol marketing could be an important policy for the protection of alcohol abstention. The IAC policy index may be a useful tool to benchmark the performance of alcohol policy in supporting alcohol abstention in high and middle-income countries.Output Status: Forthcoming/Available Onlin

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies