ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer.

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.

Serum biomarker signature is predictive of the risk of hepatocellular cancer in patients with cirrhosis.

BACKGROUND: Inflammatory and metabolic biomarkers have been associated with hepatocellular cancer (HCC) risk in phases I and II biomarker studies. We developed and internally validated a robust metabolic biomarker panel predictive of HCC in a longitudinal phase III study. METHODS: We used data and banked serum from a prospective cohort of 2266 adult patients with cirrhosis who were followed until the development of HCC (n=126). We custom designed a FirePlex immunoassay to measure baseline serum levels of 39 biomarkers and established a set of biomarkers with the highest discriminatory ability for HCC. We performed bootstrapping to evaluate the predictive performance using C-index and time-dependent area under the receiver operating characteristic curve (AUROC). We quantified the incremental predictive value of the biomarker panel when added to previously validated clinical models. RESULTS: We identified a nine-biomarker panel (P9) with a C-index of 0.67 (95% CI 0.66 to 0.67), including insulin growth factor-1, interleukin-10, transforming growth factor ß1, adipsin, fetuin-A, interleukin-1 ß, macrophage stimulating protein α chain, serum amyloid A and TNF-α. Adding P9 to our clinical model with 10 factors including AFP improved AUROC at 1 and 2 years by 4.8% and 2.7%, respectively. Adding P9 to aMAP score improved AUROC at 1 and 2 years by 14.2% and 7.6%, respectively. Adding AFP L-3 or DCP did not change the predictive ability of the P9 model. CONCLUSIONS: We identified a panel of nine serum biomarkers that is independently associated with developing HCC in cirrhosis and that improved the predictive ability of risk stratification models containing clinical factors.

Prostate cancer research: The next generation; report from the 2019 Coffey-Holden Prostate Cancer Academy Meeting.

INTRODUCTION: The 2019 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Prostate Cancer Research: The Next Generation," was held 20 to 23 June, 2019, in Los Angeles, California. METHODS: The CHPCA Meeting is an annual conference held by the Prostate Cancer Foundation, that is uniquely structured to stimulate intense discussion surrounding topics most critical to accelerating prostate cancer research and the discovery of new life-extending treatments for patients. The 7th Annual CHPCA Meeting was attended by 86 investigators and concentrated on many of the most promising new treatment opportunities and next-generation research technologies. RESULTS: The topics of focus at the meeting included: new treatment strategies and novel agents for targeted therapies and precision medicine, new treatment strategies that may synergize with checkpoint immunotherapy, next-generation technologies that visualize tumor microenvironment (TME) and molecular pathology in situ, multi-omics and tumor heterogeneity using single cells, 3D and TME models, and the role of extracellular vesicles in cancer and their potential as biomarkers. DISCUSSION: This meeting report provides a comprehensive summary of the talks and discussions held at the 2019 CHPCA Meeting, for the purpose of globally disseminating this knowledge and ultimately accelerating new treatments and diagnostics for patients with prostate cancer.

Fusion of nearby inverted repeats by a replication-based mechanism leads to formation of dicentric and acentric chromosomes that cause genome instability in budding yeast.

Large-scale changes (gross chromosomal rearrangements [GCRs]) are common in genomes, and are often associated with pathological disorders. We report here that a specific pair of nearby inverted repeats in budding yeast fuse to form a dicentric chromosome intermediate, which then rearranges to form a translocation and other GCRs. We next show that fusion of nearby inverted repeats is general; we found that many nearby inverted repeats that are present in the yeast genome also fuse, as does a pair of synthetically constructed inverted repeats. Fusion occurs between inverted repeats that are separated by several kilobases of DNA and share >20 base pairs of homology. Finally, we show that fusion of inverted repeats, surprisingly, does not require genes involved in double-strand break (DSB) repair or genes involved in other repeat recombination events. We therefore propose that fusion may occur by a DSB-independent, DNA replication-based mechanism (which we term "faulty template switching"). Fusion of nearby inverted repeats to form dicentrics may be a major cause of instability in yeast and in other organisms.

Gatekeepers of chromatin: Small metabolites elicit big changes in gene expression.

Eukaryotes are constantly fine-tuning their gene expression programs in response to the demands of the environment and the availability of nutrients. Such dynamic regulation of the genome necessitates versatile chromatin architecture. Rapid changes in transcript levels are brought about via a wide range of post-translational modifications of the histone proteins that control chromatin structure. Many enzymes responsible for these modifications have been identified and they require various metabolic cofactors or substrates for their activity. Herein, we highlight recent developments that have begun to reveal particular cellular metabolites that might in fact be underappreciated regulators of gene expression through their ability to modulate particular histone modifications.

Differences in Prediagnostic Serum Metabolomic and Lipidomic Profiles Between Cirrhosis Patients with and without Incident Hepatocellular Carcinoma.

Background: Early detection of hepatocellular carcinoma (HCC) is crucial for improving patient outcomes, but we lack robust clinical biomarkers. This study aimed to identify a metabolite and/or lipid panel for early HCC detection. Methods: We developed a high-resolution liquid chromatography mass spectrometry (LC-MS)-based profiling platform and evaluated differences in the global metabolome and lipidome between 28 pre-diagnostic serum samples from patients with cirrhosis who subsequently developed HCC (cases) and 30 samples from patients with cirrhosis and no HCC (controls). We linked differentially expressed metabolites and lipids to their associated genes, proteins, and transcriptomic signatures in publicly available datasets. We used machine learning models to identify a minimal panel to distinguish between cases and controls. Results: Among cases compared with controls, 124 metabolites and 246 lipids were upregulated, while 208 metabolites and 73 lipids were downregulated. The top upregulated metabolites were glycoursodeoxycholic acid, 5-methyltetrahydrofolic acid, octanoyl-coenzyme A, and glycocholic acid. Elevated lipids comprised glycerol lipids, cardiolipin, and phosphatidylethanolamine, whereas suppressed lipids included oxidized phosphatidylcholine and lysophospholipids. There was an overlap between differentially expressed metabolites and lipids and previously published transcriptomic signatures, illustrating an association with liver disease severity. A panel of 12 metabolites that distinguished between cases and controls with an area under the receiver operating curve of 0.98 for the support vector machine (interquartile range, 0.9-1). Conclusion: Using prediagnostic serum samples, we identified a promising metabolites panel that accurately identifies patients with cirrhosis who progressed to HCC. Further validation of this panel is required.

Frequent CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression.

We analyzed genomic data from the prostate cancer of African- and European American men to identify differences contributing to racial disparity of outcome. We also performed FISH-based studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CHD1-deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. Subclonal deletion of CHD1 was nearly three times as frequent in prostate tumors of African American than in European American men and it associates with rapid disease progression. CHD1 deletion was not associated with HR deficiency associated mutational signatures or HR deficiency as detected by RAD51 foci formation. This was consistent with the moderate increase of olaparib and talazoparib sensitivity with several CHD1 deficient cell lines showing talazoparib sensitivity in the clinically relevant concentration range. CHD1 loss may contribute to worse disease outcome in African American men.

Assessment of Patient-Derived Xenograft Growth and Antitumor Activity: The NCI PDXNet Consensus Recommendations.

Although patient-derived xenografts (PDX) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating the comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and assessing a suite of analytical tools will enhance information exchange and facilitate identification of promising novel therapies and biomarkers for guiding cancer therapy.

Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression without inducing homologous recombination deficiency.

We analyzed genomic data derived from the prostate cancer of African and European American men in order to identify differences that may contribute to racial disparity of outcome and that could also define novel therapeutic strategies. In addition to analyzing patient derived next generation sequencing data, we performed FISH based confirmatory studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CRISPR edited, CHD1 deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. We found that subclonal deletion of CHD1 is nearly three times as frequent in prostate tumors of African American men than in men of European ancestry and it associates with rapid disease progression. We further showed that CHD1 deletion is not associated with homologous recombination deficiency associated mutational signatures in prostate cancer. In prostate cancer cell line models CHD1 deletion did not induce HR deficiency as detected by RAD51 foci formation assay or mutational signatures, which was consistent with the moderate increase of olaparib sensitivity. CHD1 deficient prostate cancer cells, however, showed higher sensitivity to talazoparib. CHD1 loss may contribute to worse outcome of prostate cancer in African American men. A deeper understanding of the interaction between CHD1 loss and PARP inhibitor sensitivity will be needed to determine the optimal use of targeted agents such as talazoparib in the context of castration resistant prostate cancer.

A Pan-Cancer Patient-Derived Xenograft Histology Image Repository with Genomic and Pathologic Annotations Enables Deep Learning Analysis.

Patient-derived xenografts (PDX) model human intra- and intertumoral heterogeneity in the context of the intact tissue of immunocompromised mice. Histologic imaging via hematoxylin and eosin (H&E) staining is routinely performed on PDX samples, which could be harnessed for computational analysis. Prior studies of large clinical H&E image repositories have shown that deep learning analysis can identify intercellular and morphologic signals correlated with disease phenotype and therapeutic response. In this study, we developed an extensive, pan-cancer repository of >1,000 PDX and paired parental tumor H&E images. These images, curated from the PDX Development and Trial Centers Research Network Consortium, had a range of associated genomic and transcriptomic data, clinical metadata, pathologic assessments of cell composition, and, in several cases, detailed pathologic annotations of neoplastic, stromal, and necrotic regions. The amenability of these images to deep learning was highlighted through three applications: (i) development of a classifier for neoplastic, stromal, and necrotic regions; (ii) development of a predictor of xenograft-transplant lymphoproliferative disorder; and (iii) application of a published predictor of microsatellite instability. Together, this PDX Development and Trial Centers Research Network image repository provides a valuable resource for controlled digital pathology analysis, both for the evaluation of technical issues and for the development of computational image-based methods that make clinical predictions based on PDX treatment studies. Significance: A pan-cancer repository of >1,000 patient-derived xenograft hematoxylin and eosin-stained images will facilitate cancer biology investigations through histopathologic analysis and contributes important model system data that expand existing human histology repositories.

Checkpoint genes and Exo1 regulate nearby inverted repeat fusions that form dicentric chromosomes in Saccharomyces cerevisiae.

Genomic rearrangements are common, occur by largely unknown mechanisms, and can lead to human diseases. We previously demonstrated that some genome rearrangements occur in budding yeast through the fusion of two DNA sequences that contain limited sequence homology, lie in inverted orientation, and are within 5 kb of one another. This inverted repeat fusion reaction forms dicentric chromosomes, which are well-known intermediates to additional rearrangements. We have previously provided evidence indicating that an error of stalled or disrupted DNA replication forks can cause inverted repeat fusion. Here we analyze how checkpoint protein regulatory pathways known to stabilize stalled forks affect this form of instability. We find that two checkpoint pathways suppress inverted repeat fusion, and that their activities are distinguishable by their interactions with exonuclease 1 (Exo1). The checkpoint kinase Rad53 (Chk2) and recombination protein complex MRX(MRN) inhibit Exo1 in one pathway, whereas in a second pathway the ATR-like kinases Mec1 and Tel1, adaptor protein Rad9, and effector kinases Chk1 and Dun1 act independently of Exo1 to prevent inverted repeat fusion. We provide a model that indicates how in Rad53 or MRX mutants, an inappropriately active Exo1 may facilitate faulty template switching between nearby inverted repeats to form dicentric chromosomes. We further investigate the role of Rad53, using hypomorphic alleles of Rad53 and null mutations in Rad9 and Mrc1, and provide evidence that only local, as opposed to global, activity of Rad53 is sufficient to prevent inverted repeat fusion.

ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer.

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor and the NE splicing factor SRRM4, among others. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. OC2 also activates glucuronidation genes that irreversibly disable androgen, thereby evoking phenotypic heterogeneity indirectly by hormone depletion. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC. Our findings support enhanced efforts to therapeutically target this protein as a means of suppressing treatment-resistant disease.

Racial disparities in prostate cancer: A complex interplay between socioeconomic inequities and genomics.

The largest US cancer health disparity exists in prostate cancer, with Black men having more than a two-fold increased risk of dying from prostate cancer compared to all other races. This disparity is a result of a complex network of factors including socioeconomic status (SES), environmental exposures, and genetics/biology. Inequity in the US healthcare system has emerged as a major driver of disparity in prostate cancer outcomes and has raised concerns that the actual incidence rates may be higher than current estimates. However, emerging studies argue that equalizing healthcare access will not fully eliminate racial health disparities and highlight the important role of biology. Significant differences have been observed in prostate cancer biology between ancestral groups that may contribute to prostate cancer health disparities. Notably, relative to White men, Black men with prostate cancer exhibit increased androgen receptor signaling, genomic instability, metabolic dysregulation, and inflammatory and cytokine signaling. Immediate actions are needed to increase multi-center, interdisciplinary research to bridge the gap between social and biological determinants of prostate cancer health disparities.

Clinicogenomic characterization of prostate cancer liver metastases.

BACKGROUND: The site of prostate cancer metastasis is an important predictor of oncologic outcomes, however, the clinicogenomic characteristics associated with the site are not well-defined. Herein, we characterize the genomic alterations associated with the metastatic site of prostate cancer. METHODS: We analyzed clinical and genomic data from prostate cancer patients with metastatic disease and known metastatic sites from publicly available targeted sequencing data. RESULTS: Prostate cancer metastasis to the liver versus other sites of metastasis conferred a high hazard for death in patients with metastatic prostate cancer (HR: 3.96, 95% CI: 2.4-6.5, p < 0.0001). Genomic analysis of metastatic tissues of prostate cancer-specific genes demonstrated that liver metastases were more enriched with MYC amplification (29.5% vs. 9.8%, FDR = 0.001), PTEN deletion (42% vs. 20.8%, FDR = 0.005), and PIK3CB amplification (8.2% vs. 0.9, FDR = 0.005) compared to other sites. No point mutations were significantly associated with liver metastasis compared to other metastatic sites. CONCLUSION: Liver metastases in prostate cancer are associated with poor survival and aggressive genomic features, including MYC-amplification, PTEN-deletion, and PIK3CB-amplification. These findings could have prognostic, treatment, and trial implications.

A path to translation: How 3D patient tumor avatars enable next generation precision oncology.

3D patient tumor avatars (3D-PTAs) hold promise for next-generation precision medicine. Here, we describe the benefits and challenges of 3D-PTA technologies and necessary future steps to realize their potential for clinical decision making. 3D-PTAs require standardization criteria and prospective trials to establish clinical benefits. Innovative trial designs that combine omics and 3D-PTA readouts may lead to more accurate clinical predictors, and an integrated platform that combines diagnostic and therapeutic development will accelerate new treatments for patients with refractory disease.

The Prostate Cancer Androgen Receptor Cistrome in African American Men Associates with Upregulation of Lipid Metabolism and Immune Response.

African-American (AA) men are more likely to be diagnosed with and die from prostate cancer than European American (EA) men. Despite the central role of the androgen receptor (AR) transcription factor in prostate cancer, little is known about the contribution of epigenetics to observed racial disparities. We performed AR chromatin immunoprecipitation sequencing on primary prostate tumors from AA and EA men, finding that sites with greater AR binding intensity in AA relative to EA prostate cancer are enriched for lipid metabolism and immune response genes. Integration with transcriptomic and metabolomic data demonstrated coinciding upregulation of lipid metabolism gene expression and increased lipid levels in AA prostate cancer. In a metastatic prostate cancer cohort, upregulated lipid metabolism associated with poor prognosis. These findings offer the first insights into ancestry-specific differences in the prostate cancer AR cistrome. The data suggest a model whereby increased androgen signaling may contribute to higher levels of lipid metabolism, immune response, and cytokine signaling in AA prostate tumors. Given the association of upregulated lipogenesis with prostate cancer progression, our study provides a plausible biological explanation for the higher incidence and aggressiveness of prostate cancer observed in AA men. SIGNIFICANCE: With immunotherapies and inhibitors of metabolic enzymes in clinical development, the altered lipid metabolism and immune response in African-American men provides potential therapeutic opportunities to attenuate racial disparities in prostate cancer.

PDXNet portal: patient-derived Xenograft model, data, workflow and tool discovery.

We created the PDX Network (PDXNet) portal (https://portal.pdxnetwork.org/) to centralize access to the National Cancer Institute-funded PDXNet consortium resources, to facilitate collaboration among researchers and to make these data easily available for research. The portal includes sections for resources, analysis results, metrics for PDXNet activities, data processing protocols and training materials for processing PDX data. Currently, the portal contains PDXNet model information and data resources from 334 new models across 33 cancer types. Tissue samples of these models were deposited in the NCI's Patient-Derived Model Repository (PDMR) for public access. These models have 2134 associated sequencing files from 873 samples across 308 patients, which are hosted on the Cancer Genomics Cloud powered by Seven Bridges and the NCI Cancer Data Service for long-term storage and access with dbGaP permissions. The portal includes results from freely available, robust, validated and standardized analysis workflows on PDXNet sequencing files and PDMR data (3857 samples from 629 patients across 85 disease types). The PDXNet portal is continuously updated with new data and is of significant utility to the cancer research community as it provides a centralized location for PDXNet resources, which support multi-agent treatment studies, determination of sensitivity and resistance mechanisms, and preclinical trials.

Androgen receptor signaling inhibitors: post-chemotherapy, pre-chemotherapy and now in castration-sensitive prostate cancer.

Based on pioneering work by Huggins, Hodges and others, hormonal therapies have been established as an effective approach for advanced prostate cancer (PC) for the past eight decades. However, it quickly became evident that androgen deprivation therapy (ADT) via surgical or medical castration accomplishes inadequate inhibition of the androgen receptor (AR) axis, with clinical resistance inevitably emerging due to adrenal and intratumoral sources of androgens and other mechanisms. Early efforts to augment ADT by adding adrenal-targeting agents (aminoglutethimide, ketoconazole) or AR antagonists (flutamide, bicalutamide, nilutamide, cyproterone) failed to achieve overall survival (OS) benefits, although they did exhibit some evidence of limited clinical activity. More recently, four new androgen receptor signaling inhibitors (ARSIs) successfully entered clinical practice. Specifically, the CYP17 inhibitor abiraterone acetate and the second generation AR antagonists (enzalutamide, apalutamide and darolutamide) achieved OS benefits for PC patients, confirmed the importance of reactivated AR signaling in castration-resistant PC and validated important concepts that had been proposed in the field several decades ago but had remained so far unproven, including adrenal-targeted therapy and combined androgen blockade. The past decade has seen steady advances toward more comprehensive AR axis targeting. Now the question is raised whether we have accomplished the maximum AR axis inhibition possible or there is still room for improvement. This review, marking the 80-year anniversary of ADT and 10-year anniversary of successful ARSIs, examines their current clinical use and discusses future directions, in particular combination regimens, to maximize their efficacy, delay emergence of resistance and improve patient outcomes.

Inhibition of GATA2 in prostate cancer by a clinically available small molecule.

Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and is linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity and proliferation assays, global gene expression analysis, RT-qPCR, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo. Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell-cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair, and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC.

Novel genomic signature predictive of response to immune checkpoint blockade: A pan-cancer analysis from project Genomics Evidence Neo-plasia Information Exchange (GENIE).

BACKGROUND: High tumor mutation burden (TMB) and total mutation count (TMC) can be predictive of better response to immune checkpoint blockade (ICB). Nevertheless, TMB and TMC are limited by variation across cancers and inconsistent definitions due to different profiling methods (targeted vs whole genome sequencing). Our objective was to identify genomic alterations (GAs) associated with ICB response and builds a novel genomic signature predictive of ICB response, independent of TMB/TMC. METHODS: This was a pan-cancer next generation sequencing (NGS)-association study using January 2014-May 2016 data from AACR Project Genomics Evidence Neo-plasia Information Exchange (GENIE). Participants included 6619 patients with metastatic or un-resectable cancer across 9 cancer types (including 1572 ICB-treated patients). GA data was collected using next-generation sequencing (NGS) assays and downloaded from cbioportal.org. Predictive analyses for ICB response were performed to develop the signature (ImmGA). RESULTS: GAs in 16 genes were associated with improved OS in ICB-treated patients (p < 0.005). 13 GAs were associated with an OS benefit in ICB-treated patients (Pinteraction < 0.05); these genes composed the ImmGA signature. High ImmGA score (≥2 alterations out of 13 predictive GAs) was associated with better OS in ICB-treated patients (AHR:0.67, 95%CI [0.6-0.75], p = 1.4e-12), even after accounting for TMC (Pinteraction = 8e-16). High ImmGA was associated with better OS in ICB-treated patients across most cancers and across different ICB treatment modalities. CONCLUSION: A novel signature predictive of ICB response (ImmGA) was developed from 13 GAs. Further investigation of the utility of ImmGA for treatment and trial selection is warranted.