Evolutionary dynamics of recurrent hepatocellular carcinoma under divergent immune selection pressures.

Hepatocellular carcinoma (HCC) is a highly lethal, aggressive malignancy. Little is known about the evolutionary trajectories of HCC and how clinical decision-making could be informed based on biopsies of the initial tumour. Here, we report the whole-exome sequencing of a unique series of resected HCC tumours and matched recurrences.

Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia.

Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature.

The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population.

Introduction: The imbalance between Th17 and regulatory T cells in inflammatory bowel diseases (IBD) promotes intestinal epithelial cell damage. In this scenario, T helper cell lineage commitment is accompanied by dynamic changes to the chromatin that facilitate or repress gene expression.

Methods: Here, we characterized the chromatin landscape and heterogeneity of intestinal and peripheral CD4 T cellsfrom IBD patients using in house ATAC-Seq and single cell RNA-Seq libraries.

Cerebrospinal fluid methylome-based liquid biopsies for accurate malignant brain neoplasm classification.

Background: Resolving the differential diagnosis between brain metastases (BM), glioblastomas (GBM), and central nervous system lymphomas (CNSL) is an important dilemma for the clinical management of the main three intra-axial brain tumor types. Currently, treatment decisions require invasive diagnostic surgical biopsies that carry risks and morbidity. This study aimed to utilize methylomes from cerebrospinal fluid (CSF), a biofluid proximal to brain tumors, for reliable non-invasive classification that addresses limitations associated with low target abundance in existing approaches.

H3K9 methylation drives resistance to androgen receptor-antagonist therapy in prostate cancer.

Antiandrogen strategies remain the prostate cancer treatment backbone, but drug resistance develops. We show that androgen blockade in prostate cancer leads to derepression of retroelements (REs) followed by a double-stranded RNA (dsRNA)-stimulated interferon response that blocks tumor growth. A forward genetic approach identified H3K9 trimethylation (H3K9me3) as an essential epigenetic adaptation to antiandrogens, which enabled transcriptional silencing of REs that otherwise stimulate interferon signaling and glucocorticoid receptor expression.

DNA methylation-based prognostic subtypes of chordoma tumors in tissue and plasma.

Background: Chordomas are rare malignant bone cancers of the skull-base and spine. Patient survival is variable and not reliably predicted using clinical factors or molecular features. This study identifies prognostic epigenetic chordoma subtypes that are detected noninvasively using plasma methylomes.

DNA hypomethylating agents increase activation and cytolytic activity of CD8 T cells.

We demonstrate that DNA hypomethylating agent (HMA) treatment can directly modulate the anti-tumor response and effector function of CD8 T cells. In vivo HMA treatment promotes CD8 T cell tumor infiltration and suppresses tumor growth via CD8 T cell-dependent activity. Ex vivo, HMAs enhance primary human CD8 T cell activation markers, effector cytokine production, and anti-tumor cytolytic activity.

Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency.

Cancer therapies that target epigenetic repressors can mediate their effects by activating retroelements within the human genome. Retroelement transcripts can form double-stranded RNA (dsRNA) that activates the MDA5 pattern recognition receptor. This state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses.

Author Correction: Detection of renal cell carcinoma using plasma and urine cell-free DNA methylomes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors.

Purpose: To evaluate whether administration of the oral DNA hypomethylating agent CC-486 enhances the poor response rate of immunologically 'cold' solid tumors to immune checkpoint inhibitor durvalumab.

Experimental Design: PD-L1/PD-1 inhibitor naïve patients with advanced microsatellite stable colorectal cancer; platinum resistant ovarian cancer; and estrogen receptor positive, HER2 negative breast cancer were enrolled in this single-institution, investigator-initiated trial. Two 28 day regimens, regimen A (CC-486 300 mg QD Days 1-14 (cycles 1-3 only) in combination with durvalumab 1500 mg intravenous day 15) and regimen B (CC-486 100 mg QD days 1-21 (cycle 1 and beyond), vitamin C 500 mg once a day continuously and durvalumab 1500 mg intravenous day 15) were investigated.

Detection of renal cell carcinoma using plasma and urine cell-free DNA methylomes.

Improving early cancer detection has the potential to substantially reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a highly sensitive assay capable of detecting early-stage tumors. We report accurate classification of patients across all stages of renal cell carcinoma (RCC) in plasma (area under the receiver operating characteristic (AUROC) curve of 0.

Detection and discrimination of intracranial tumors using plasma cell-free DNA methylomes.

Definitive diagnosis of intracranial tumors relies on tissue specimens obtained by invasive surgery. Noninvasive diagnostic approaches provide an opportunity to avoid surgery and mitigate unnecessary risk to patients. In the present study, we show that DNA-methylation profiles from plasma reveal highly specific signatures to detect and accurately discriminate common primary intracranial tumors that share cell-of-origin lineages and can be challenging to distinguish using standard-of-care imaging.

Using epigenetic data to estimate immune composition in admixed samples.

Variation in cell-type decomposition can be of interest to changes in biology by themselves, or a confounder in comparing admixed samples with different phenotypes. Here, I present and review various algorithms that may be used for purposes of deconvolving epigenomic data from admixed samples to yield estimates that may be factored into downstream analyses. More specifically, I present a protocol based on an adaptation of the CIBERSORT algorithm, previously developed for gene-expression, to methylation data.

NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors.

Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8 T cells from tumors (not CD4 T cells or macrophages); CD8 T-cell exclusion was similarly present in CAF-rich human tumors.

GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment.

General control nonderepressible 2 (GCN2) is an environmental sensor controlling transcription and translation in response to nutrient availability. Although GCN2 is a putative therapeutic target for immuno-oncology, its role in shaping the immune response to tumors is poorly understood. Here, we used mass cytometry, transcriptomics, and transcription factor-binding analysis to determine the functional impact of GCN2 on the myeloid phenotype and immune responses in melanoma.

Epigenetic therapy in immune-oncology.

DNA methylation inhibitors have become the mainstay for treatment of certain haematological malignancies. In addition to their abilities to reactivate genes, including tumour suppressors, that have acquired DNA methylation during carcinogenesis, they induce the expression of thousands of transposable elements including endogenous retroviruses and latent cancer testis antigens normally silenced by DNA methylation in most somatic cells. This results in a state of viral mimicry in which treated cells mount an innate immune response by turning on viral defence genes and potentially expressing neoantigens.

TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure.

The extracellular matrix (ECM) is a key determinant of cancer progression and prognosis. Here we report findings from one of the largest pan-cancer analyses of ECM gene dysregulation in cancer. We define a distinct set of ECM genes upregulated in cancer (C-ECM) and linked to worse prognosis.

Author Correction: Pan-cancer deconvolution of tumour composition using DNA methylation.

The original version of this Article contained an error in Figure 4. In panel a, the colour code for hot and cold clusters was inadvertently inverted. In the correct version of panel a, the hot clusters are blue and the cold clusters are yellow.

Pan-cancer deconvolution of tumour composition using DNA methylation.

The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a DNA methylation-based approach to tumour cell fraction deconvolution, we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: 'immune hot' and 'immune cold', which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity and oncogenic driver events.

Frequent HPV-independent p16/INK4A overexpression in head and neck cancer.

Objectives: p16 (p16) is the most widely used clinical biomarker for Human Papillomavirus (HPV) in head and neck squamous cell cancer (HNSCC). HPV is a favourable prognostic marker in HNSCC and is used for patient stratification. While p16 is a relatively accurate marker for HPV within the oropharynx, recent reports suggest it may be unsuitable for use in other HNSCC subsites, where a smaller proportion of tumors are HPV-driven.