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• Epithelioid haemangioendothelioma (EHE) case series from the Stafford Fox Rare Cancer Program

  Nine EHE cases with comprehensive histologic and molecular profiling from the Walter and Eliza Hall Institute of Medical Research Stafford Fox Rare Cancer Program were collated via nation-wide referral to the Australian Rare Cancer Portal. Molecular analysis of RNA, DNA or both was possible in seven of nine cases. Survival was highly variable and unrelated to molecular profile. DNA sequences for two cases are deposited here.

  Study EGAS00001007474

• RNA sequencing in primary human macrophages overexpressing ETS2

  We investigated an intergenic haplotype on chr21q22, linked to five different inflammatory diseases, and discovered a mechanism that orchestrates macrophage responses during chronic inflammation. We delineated how the risk haplotype increases expression of the causal gene, ETS2, and demonstrated that ETS2 is necessary for inflammatory macrophage effector functions. To establish whether ETS2 is sufficient to drive inflammatory responses, we overexpressed ETS2 in a dose-dependent manner and performed RNA-sequencing to characterise the transcriptional effects.

  Study EGAS00001007554

• Profiling heterogeneity in Human derived IPSC-neurons (2020-05-18)

  The impact of genetic variants on molecular pathways that give rise to neurodegenerative diseases such as Alzheimer's and Parkinson's is best elucidated in the appropriate cell types and molecular contexts. Existing studies have focused on bulk profiling of mixed cell types, but have ignored assaying genetic effects across development and cell differentiation. At the core of this proposal is the idea to use single-cell assays to study genetic effects during differentiation of dopaminergic and cortical neurons to identify the sequence of molecular events from variants to healthy and diseased cell states in a cell-specific manner. 1) This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2020-05-18.

  Dataset EGAD00001006157

• WGS and Avenio Surveillance Panel data to previously submitted data under study number EGAS00001004276 of ALK-rearranged lung cancer

  Some data was previously submitted data under study number EGAS00001004276. In this new dataset we provide additional WGS and Avenio Surveillance Panel data. We utilized 43 ALK+ NSCLC patients receiving targeted ALK therapy to evaluate ctDNA levels based on matched panel-based targeted next generation sequencing (tNGS) and untargeted shallow whole genome sequencing (sWGS). For the Avenio panel the sequencing was done on Illumina NextSeq 550 paired end 150 bp, for WGS the sequencing was done on Illumina HiSeq 4000, partly with KAPA_Hyper_Prep_Kit. In this dataset there are 132 WGS tumor samples and 134 panel sequencing data of plasma.

  Dataset EGAD00001007818

• RNA sequencing data of in vitro differentiated megakaryocyte cells transduced with E527K and WT SRC

  RNA sequencing data of in vitro differentiated megakaryocyte cells transduced with E527K and WT SRC. CD34+ hematopoietic stem cells (HSC) were isolated from healthy controls before transduction with WT-SRC and E527K-SRC lentiviral vectors in triplicate and differentiation to MK. Three replicates each of two pools were generated for both WT and E527K SRC transduced cells, resulting in 3 WT pool 1 samples, 3 WT pool 2 samples, 3 E527K pool 1 samples and 3 E527K pool 2 samples for a total of 12 samples. RNA was extracted and sequenced with following parameters: Platform: Illumina HiSeq4000, Library Prep Kit: TruSeq stranded mRNA, Sequencing Kit: Illumina HiSeq4000 100 cycles (76-8-8-7), Fragments: single end / fr-firststrand.

  Dataset EGAD00001008356

• Cholangiocarcinoma

  Arcagen is an EORTC/SPECTA pan-European project that aims to recruit 1000 rare cancer patients from different tumour domains of EURACAN. This study collected samples from advanced or metastatic rare cancer from patients older than 12, and analysed them using Foundation Medicine next-generation sequencing (NGS) panels (FoundationOne CDx for FFPE samples or FoundationOne Liquid CDx for blood samples). Here we are submitting two datasets that contain NGS files from gastrointestinal rare cancers (n=119): - Dataset 2 (87 patients): Intra-hepatic cholangiocarcinoma (n=47), Extra-hepatic, cholangiocarcinoma (n=16), Not specified Cholangiocarcinoma (n=9), Small bowel adenocarcinoma (n=6) and other rare GI cancer (n=9)

  Dataset EGAD00001008968

• Induction of trained immunity by influenza vaccine: impact on COVID-19

  Cryopreserved PBMCs from 10 individuals before and after vaccination were used to perform single cell RNA sequencing. Equal number of cells per individual were pooled together (5 individuals per pool) and single-cell RNA sequencing was performed in paired-end mode on NovaSeq 6000 (Illumina) with a depth of 50,000 reads per cell. DNA was isolated from PBMCs and then used for genotyping by Illumina GSA Beadchip. This dataset contains the fastq sequence files, genotypes of the donors used for demultiplexing the pools and files indicating the linkages between individuals, pools and fastq files. The number of samples listed by EGA does not match the actual number of samples due to limitations on the upload scheme used.

  Dataset EGAD00001007827

• Whole exome sequencing study of cholesteatoma patients from affected families

  This study used whole exome sequencing on 21 patients with cholesteatoma from 10 families in order to identify variants that may attribute to cholesteatoma aetiology. Exomes were enriched for using hybridisation selection and subject to DNA-sequencing. This datasets is formed of two batches as they were sequencing at different times. Batch-1 exomes were selected for using Nimblegen capture (4-plex) and sequenced on Illumina Hiseq 4000 and batch-2 was exome selected using Agilent SureSelect Human All Exon v6 and sequenced on the Illumina NovaSeq 6000. All samples within the same family were processed within the same batch. This dataset is comprised on BAM files mapped using cgpMAP v3.2.0 (bwa-mem) using the GRCh38.

  Dataset EGAD00001008671

• Somatic mutation and clonal evolution in premalignant lung disease - WGS (2020-01-15)

  Cancer is a genetic disease caused by an accumulations of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from the lung tissue of individuals with a variety of lung diseases (COPD, UIP, IPF, Emphysema, pulmonary hypertension). This will allow us to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. Smoking is a large risk factor for developing many of these lung diseases so we are particularly keen to determining whether there is evidence of a smoking signature in these patients. . This dataset contains all the data available for this study on 2020-01-15.

  Dataset EGAD00001005786

• Panel amplicon sequencing data of COVID-19 patients

  Amplicon sequencing data for 90 patients hospitalized for COVID-19. to general ward. Patients had a median age of 60.5 (52.0 – 69.3) years and were overweighted (Body mass index: 28.4 (24.4 – 32.6) kg/m2). 35.6% of the cohort were female. The following genes were sequenced on a NovaSeq600 instrument with an Enrichment based library preparation (IDT-xGEN) with a median coverage of 2000x: ABL1, ASXL1, ATRX, BCOR, BCORL1, BRAF, CALR, CBL, CBLB, CBLC, CDKN2A, CEBPA, CSF3R, CUX1, DNMT3A, ETV6, EZH2, FBXW7, FLT3, FLT3-ITD, GATA1, GATA2, GNAS, GNB1, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, MPL, MYD88, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PPM1D, PTEN, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC1A, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, WT1, ZRSR2

  Dataset EGAD00001009416

• An IL-1β driven neutrophil-stromal cell axis fosters a BAFF-rich microenvironment in multiple myeloma

  This depository contains data from two bulk RNA sequencing experiments: 1) Bulk RNA sequencing data of peripheral blood neutrophils from healthy donors cultured with a) human adipose-derived stromal cells (ADSC) as a model for mesenchymal stromal cells (MSC), and b) IL-1β stimulated ADSC as a model for inflammatory MSC as found in multiple myeloma (MM). 2) Bulk RNA sequencing data from ADSCs cultured a) without stimuli, b) with recombinant human IL-1β, c) with supernatant from iMSC-like cells, d) with neutrophils previously cultured with MSC, e) with neutrophils previously cultured with iMSC, f) with neutrophils previously cultured with iMSC in the presence of anti-human IL-1β or g) with neutrophils previously cultured with iMSC in the presence of an isotype control.

  Dataset EGAD00001010080

• Timing chromosomal amplification events using patterns of somatic mutations in high hyperdiploid acute lymphoblastic leukemia

  This dataset included 19 paired diagnostic and remission samples with high hyperdiploid acute lymphoblastic leukemia (ALL) that were collected from four different cohorts: the Division of Clinical Genetics, Lund University, Sweden. All samples were subjected to whole genome sequencing using the Illumina HiSeqX platform. Paired-end sequencing (2x150bp) was done to ~60x coverage for diagnostic samples and ~30x coverage for remission samples. The paired-end reads were aligned to the human reference genome GRCh37 (ftp://ftp.ncbi.nlm.nih.gov/genomes/refseq/vertebrate_mammalian/Homo_sapiens/all_assembly_versions/GCF_000001405.25_GRCh37.p13/GCF_000001405.25_GRCh37.p13_genomic.fna.gz) by the Burrows-Wheeler Aligner tool (version 0.7.17). Duplicate reads marking and local realignment were performed by GATK (version 4.0.11.0).

  Dataset EGAD00001010103

• NOTCH1 fusion genes in pediatric T-cell lymphoblastic lymphoma hallmark a common high-risk subgroup with blood TARC levels as possible biomarker

  T-cell lymphoblastic lymphoma (T-LBL) is a common pediatric malignancy accounting for approximately 20% of the non-Hodgkin lymphomas during childhood. Survival rates of T-LBL are ~80%, but outcome after relapse is dismal, with salvage rates reaching only ~15. Considering the extremely poor prognosis after relapse and absence of clinically relevant high-risk genetics, there is an urgent need for the identification of molecular risk factors and new prognostic biomarkers in T-LBL, as well as identification of new therapeutic strategies. In this study we present a novel entity of high-risk pediatric T-LBL patients characterized by previously unknown NOTCH1 gene fusions and highly elevated blood TARC levels

  Dataset EGAD00001015255

• single cell RNA-seq of bone marrow from infants with MLL-rearranged Acute Lymphoblastic Leukemia by single cell RNA-sequencing

  This dataset contains two experiments. 1) Single cell RNA-seq of diagnostic samples from patients with MLL-rearranged infant ALL that underwent relapse or not (samples ending in R relapsed, samples ending in N did not). For some of the patients, multiple indipendent plates were produced (each plate is a sample). 2) in vitro prednisolone exposure experiment. diagnostic bone marrow samples from patient 4662R were cultured for three days with and without prednisolone. Single cell experiments were conducted according to Muraro et al (cell systems, 2016, doi:10.1016/j.cels.2016.09.002). Cell barcodes and UMI sequences are embedded in the header of each fastq entry. Cell barcodes irrelevant to this experiment were removed before submission.

  Dataset EGAD00001005461

• Variant calling analysis of cfDNA whole exome sequencing in neuroblastoma

  This dataset contains VCF files from a variant calling analysis of 19 neuroblastoma patients. WES or WGS data of the primary tumor were compared to WES cfDNA analysis at the time of diagnosis and at a 2nd timepoint (complete remission, partial remission, disease progression or relapse). For 4 patients, WGS of germline, tumor at diagnosis and tumor at relapse DNA was performed on Illumina HiSeq2500, with 100-bp paired-end reads. For the other patients, WES was performed using either an AgilentSureSelect Human All Exon v5 or a Roche Nimblegen SeqCap EZ Exome V3 kit on Illumina HiSeq2000, with 100-bp paired-end reads. SNVs observed in any of the primary tumors or cfDNA samples studied by WES were targeted using a capture sequencing panel at all intermediate time points.

  Dataset EGAD00001003803

• BAM files: Brain transcriptome of hereditary cerebral haemorrhage with amyloidosis–Dutch type (HCHWA-D)

  cDNA depleted RNA (500ng total RNA input) was fragmented to 150-200 nucleotides in first strand buffer for 3 minutes at 94°C. Random hexamer primed first strand was generated in presence of dATP, dGTP, dCTP and cTTP. Second strand was generated using dUTP instead of dTTP to tag the second strand. Subsequent steps to generate the sequencing libraries were performed with the KAPA HTP Library Preparation Kit for Illumina sequencing with minor modifications, i.e., after indexed adapter ligation to the dsDNA fragments, the library was treated with USER enzyme (NEB_M5505L) in order to digest the second strand derived fragments. After amplification of the libraries, samples with unique sample indexes were pooled and sequenced paired-end 2x50bp on a HiSeq2500 system following standard Illumina guidelines.

  Dataset EGAD00001003806

• Genome Diversity in Africa Project - ancient samples - standard libraries

  Given the central importance of Africa to studies of human origins, genetic diversity and disease susceptibility, large-scale and representative characterisation of genetic diversity in Africa is needed. Analyses of ancient DNA from Africa would complement sequencing of modern African populations and provide unique opportunities to transform our understanding of the pre-history of the region. This approach would greatly refine our understanding of population structure and gene flow in Africa and globally, including genetic signatures of ancient admixture. This low coverage sequencing experiment will allow us to test and refine our pipeline for ancient DNA sequencing. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001002211

• Miseq (18S) analysis of spiked placental tissue samples

  We spiked a small number of placental tissue samples with different combinations of Candida albicans, Plasmodium falciparum, Toxoplasma gondii, Human Cytolomega virus and Salmonella bongori (various combination of the equivalents of 1, 10, 100, 1000 and 10000 genome copies). A DNA isolation was performed on these spiked samples and the resulting DNA was subsequently sequenced by MiSeq (18S). These same samples were also analysed by X Ten to allow for a sensitivity comparison of the two methods of the eukaryotic spiked signals (Candida albicans, Plasmodium falciparum and Toxoplasma gondii). In addition, non-spiked placental samples from 50 cases of Fetal Growth Restriction (FGR) (+ matched healthy controls) and 49 cases of Preeclampsia (+ matched healthy controls) and 100 preterm cases were analyzed for their non-human eukaryotic content.

  Dataset EGAD00001004197

• Autozygosity pilot - QMUL

  The offspring of first cousin marriages have ~6% of their genome autozygous, i.e. homozygous identical by descent, or even more if there was further consanguinity in their ancestry. In the UK there are large populations with very high first cousin marriage rates of 20-50%. Sequencing the exomes of a sample of these individuals has the potential both to support genetic health programmes in these populations, and to provide genetic research information about rare loss of function mutations. This pilot study based on existing British-Pakistani cohort samples will identify homozygous individuals for almost all variants down to an allele frequency around 1%, plus individuals carrying hundreds of new homozygous rare loss-of-function variants, and will support development of community relations and ethics for a wider study currently being designed. The data deposited in the EGA consists of low coverage whole exome sequencing on these samples.

  Dataset EGAD00001001027

• single-cell RNA-seq Case-Control study of children progressing to Type1 diabetes

  It was a single-cell RNA sequencing study on the PBMC samples from four Finnish children at risk of developing Type 1 diabetes and their gender age and HLA matched control children. All four Case children were positive for multiple islet specific autoantibodies and two of them also progressed to clinical disease during the follow up whereas the control children remain negative for all autoantibodies. Single-cell analysis confirmed some of the signatures obtained from the bulk data. It identified that high IL32 in case samples in the bulk RNA-seq was contributed mainly by activated T cells and NK cells. Trajectory analysis of the scRNA-seq data suggested that IL32 expression increased as the T cells moved towards activated state.

  Dataset EGAD00001005768

• Stratton__WGS___RCC___Japan

  The Stratton team uses DNA sequencing for somatic mutations to advance understanding of the causes of cancer. In particular, the investigation of “mutational signatures”, which report the mutational processes operative over the lifetime of each individual, to understand whether they are generated by endogenous or exogenous exposures and the extent to which these vary between human populations. Our work brings together global cancer epidemiology and genomics and is particularly characterised by large-scale multinational studies.

  Study EGAS00001008001

• Acral Melanoma PDXs from the admixed Brazilian Population - Patient Derived Xenograft samples VCF files with somatic SNV and INDELs - Whole exome sequencing data

  Raw, flagged and annotated VCF files with somatic calls made with CavEMan and Pindel for Patient Derived Xenograft samples. Variant effect prediction was run with Ensembl VEP v103. Acral melanoma (AM) is an aggressive melanoma subtype with limited therapeutic options and poor outcomes. In non-European descent and admixed populations, like in Latin America, it can account for a significant proportion of cutaneous melanoma cases. Here, we performed comprehensive genomic and functional profiling of AM from a uniquely diverse Brazilian cohort. Whole-exome and transcriptome sequencing was performed on both tumours and patient-derived xenograft (PDX) samples. The PDX were obtained from a comprehensive collection of patient-derived xenograft (AM-PDX) models that we established which faithfully retained the histopathological and genomic features of the original tumours.

  Dataset EGAD00001015749

• Development and Validation of a Disability Severity Index for Charcot-Marie-Tooth Disease (CMT)

  In Charcot-Marie-Tooth Disease (CMT) or inherited neuropathy research studies, it is the researcher who has selected what they believe to be important markers of impairment in function in patients. For example, it has been inferred that the wearing of ankle-foot-orthosis (AFOs), the use of walking aids such as canes, or the use of wheelchairs, are appropriate markers for “mild”, “moderate” or “severe” disability, respectively. Whether patients agree with this classification is unknown. By understanding what patients classify as mild, moderate and severe disability in CMT, we will know what our treatments need to target, to have a meaningful impact on the patients' functional status. Primary objective: The purpose of this study is to compare patient and healthcare provider impressions of what constitutes mild, moderate and severe disability in CMT. Target population: 200 patients who have self-registered at the Inherited Neuropathy Consortium Contact Registry, a web-based contact registry developed and supported by the Data Management and Coordinating Center (DMCC) for the Rare Diseases Clinical Research Consortium (RDCRN), located at the University of South Florida, and 200 health care professionals attending conferences about CMT, such as the 4th International CMT Consortium to be held in Potomac, Maryland, June 29-July 1, 2011 and the MDA Clinic Directors meeting in Las Vegas, NV March 4-7, 2012. Methods: A brief, anonymous, 20-item survey, in which we measure what the physician and the patient think are important indicators of disability in CMT, will be distributed by paper to 200 health care professionals, and via an online link to 200 patients self-registered with the RDCRN contact registry. Out of the 200 patients, approximately 25 patients will be requested to take the survey twice in a 2 to 4 week period. Analysis: We will measure the agreement between items in the physician and patient groups, and use items with high agreement in a Disability Severity Index.

  Study phs001295

• Genome-Wide Association Study of Hypertriglyceridemia in Mexicans

  Coronary artery disease (CAD) is the number one cause of death and mortality world-wide. High levels of serum triglycerides (TGs) and low levels of serum high-density lipoprotein cholesterol (HDL-C) are major risk factors for CAD. Previous epidemiological studies have shown that these two lipid disturbances are highly common dyslipidemias in Mexicans. However, the genetic factors underlying high serum TGs and low HDL-C are underinvestigated and poorly identified in Mexicans. As the Mexican-American and the genetically related Latin-American populations represent the fastest growing minority in the United States, elucidation of the unknown genetic factors influencing the increased susceptibility of Mexicans to these common dyslipidemias is of great relevance to these U.S. minorities and the American healthcare system. This study is a research collaboration between investigators at the University of California, Los Angeles (UCLA) and Instituto Nacional de Ciencias Médicas y Nutrición (INCMN), Mexico City, to perform a two-stage genome-wide association study (GWAS) for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (Weissglas-Volkov et al. 2013, PMID: 23505323). This study was funded by an RO1 grant from NIH/NHLBI (PI Paivi Pajukanta; PI of the subaward Teresa Tusie-Luna). In stage 1 of the GWAS, we tested all GWAS SNPs from the Illumina Infinium Human610-Quad platform that passed quality control for association in ~2,200 hypertriglyceridemia cases and controls. In stage 2, we genotyped the ~1,200 positive signals of stage 1 in additional ~2,200 hypertriglyceridemia cases and controls, and performed a combined analysis of the two stages to identify genome-wide significant variants. The subjects were recruited at the INCMN. The DNA isolation and clinical laboratory measurements of the case-control study samples were performed at INCMN using standardized procedures. Genotyping and statistical analyses of the data were performed at UCLA. A summary of this GWAS can be found in Weissglas-Volkov et al. 2013 Journal of Medical Genetics, PMID: 23505323. Briefly, using the two-stage GWAS design, we identified a novel Mexican-specific genome-wide significant locus for serum TG levels close to the Niemann-Pick type C1 protein (NPC1) gene (Weissglas-Volkov et al. 2013, PMID: 23505323). Of the European lipid GWAS loci, three TG loci (APOA5, GCKR, and LPL) and four HDL-C loci (ABCA1, CETP, LIPC and LOC55908) resulted in genome-wide significant signals in Mexicans. Furthermore, our cross-ethnic mapping narrowed three European TG GWAS loci, APOA5, MLXIPL, and CILP2 that exhibited long range LD and a large number of candidate SNPs in the European GWAS scan. In the apolipoprotein A1C3A4A5 gene cluster region, the cross-ethnic fine mapping and LD comparisons reduced the number of candidate variants to one SNP, rs964184. We also found that although 52% of the associations from European lipid GWAS meta-analysis could be generalized to Mexicans, in 82% of the European GWAS loci, a different variant other than the European lead SNP provided the statistically strongest evidence of association in the Mexican scan (Weissglas-Volkov et al. 2013, PMID: 23505323). Taken together, our Mexican GWAS for lipids identified a novel Mexican-specific locus for high serum TGs; restricted three European GWAS loci; and investigated which European lipid GWAS variants extend to the Mexican population (Weissglas-Volkov et al. 2013, PMID: 23505323). This NHLBI sponsored RO1 project aimed to identify genetic variants contributing to serum lipid levels in Mexicans. In addition to de-identified genome wide genotypic data, a selected list of de-identified phenotypic data related to hypertriglyceridemia and related metabolic traits are also available in dbGaP.

  Study phs000618

• PAK4 inhibition improves PD-1 blockade immunotherapy

  Introduction with rationale and aims for study Immune checkpoint blockade therapies have significantly altered the current landscape of cancer treatment. However, this immunotherapy still fails more often than it succeeds. There are now evidences that the lack of tumour infiltration by immune cells is the main mechanism of primary resistance to PD‐1 blockade therapies for cancer. It has been postulated that cancer cell‐intrinsic mechanisms may actively exclude T cells from tumours, suggesting that the finding of actionable molecules that could be inhibited to increase T cell infiltration may synergize with checkpoint inhibitor immunotherapy. With the idea of finding potential drivers of immune exclusion, we performed RNA sequencing analysis of biopsies from melanoma patients and compared the transcriptomic differences of samples that where infiltrated with those that did not have immune infiltration. Methods RNAseq analysis of gene expressions on biopsies from melanoma patients treated with checkpoint blockade were analysed. We focused on the variable of "infiltration: yes or no,", e.g. tumors that were well infiltrated by immune cells with those that kept immune cells out. Sequencing revealed a list of genes whose expression differed between the infiltrated and noninfiltrated tumors. The kinase PAK4 stood out as a good candidate for inhibition treatment in the future as it was consistently enriched in the samples without immune infiltration. To test whether immunotherapy would work better if we deleted PAK4, we first knocked out PAK4, using CRISPR‐Cas9, in the ‐resistant melanoma cell line, B16. Then they injected the melanoma cells into mice and observed that PAK4 KO tumours now responded to PD‐1 blockade. In order to elucidate whether pharmacological inhibition of PAK4 could recapitulate the results observed in the B16 PAK4 KO tumours, we obtained the PAK4 inhibitor, KPT-9274, from Karyopharm Therapeutics. Indeed, inhibiting PAK4 in combination with anti‐PD‐1 immunotherapy significantly slowed the growth of the B16 melanomas more than either drug alone. Results and Conclusions Transcriptomic analysis of melanoma tumors that were well infiltrated by immune cells with those that kept immune cells out revealed a list of genes whose expression differed between the infiltrated and non-infiltrated tumours. The result suggests that p21 activated kinase 4 (PAK4) is enriched in non-responding tumour biopsies with low T cell and dendritic cell infiltration. In addition, PAK4 decreased WNT activity, a signalling pathway that has previously been involved in immune exclusion. In mouse models, genetic deletion of PAK4 increased T cell infiltration and reversed resistance to PD‐1 blockade in a CD8 T cell-dependent manner. Furthermore, combination of with the PAK4 inhibitor, KPT-9274, improved anti‐tumour responses compared to anti‐PD‐1 alone. Therefore, high PAK4 expression is correlated with low T cell and dendritic cell infiltration and lack of response to PD‐1 blockade, which could be reversed with PAK4 inhibition. The data establish a rationale for targeting this kinase with inhibitors in combination with immune checkpoint inhibitors for patients. Future work and data that we can anticipate for this study Oncogenic signalling pathways and specially the WNT signalling pathway, have been associated with lack of immune infiltration and resistance to PD‐1 blockade therapies. Here, we show that PAK4 overcome resistance to PD‐1 blockade while significantly decreases WNT signalling activity. Therefore, it constitutes the first potential druggable target that is able to reverse oncogenic driven immune cell exclusion. However, the fully mechanism whereby PAK4 sensitizes tumours to immunotherapy remains to be fully elucidated. It is necessary to address whether PAK4 inhibition overcomes resistance through WNT signalling inhibition or if other signalling pathways are involved in the observed phenotype.

  Study phs001919