Epigenetic silencing of Th1 type chemokines shapes tumor immunity and immunotherapy

Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8+ T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.

• Publication year

  2015

• Venue

  Nature

• Publication date

  2015-09-02

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/nature15520PMID 26503055PMCID 4779053
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer

  2015cited by this paper
• Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity

  2015cited by this paper
• Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma

  2014cited by this paper
• The polycomb repressive complex 2 governs life and death of peripheral T cells.

  2014cited by this paper
• PD-1 blockade induces responses by inhibiting adaptive immune resistance

  2014cited by this paper
• Checkpoint Blockade Cancer Immunotherapy Targets Tumour-Specific Mutant Antigens

  2014cited by this paper
• Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer

  2014cited by this paper
• IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L.

  2014cited by this paper
• CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia

  2013cited by this paper
• Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2.

  2013cited by this paper
• Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host

  2013cited by this paper
• A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response

  2012cited by this paper
• EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations

  2012cited by this paper
• The blockade of immune checkpoints in cancer immunotherapy

  2012cited by this paper
• The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming

  2012cited by this paper
• Decade-Long Safety and Function of Retroviral-Modified Chimeric Antigen Receptor T Cells

  2012cited by this paper
• Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells

  2012cited by this paper
• Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2

  2012cited by this paper
• Memory, Visual Discrimination Performance, and the Human Hippocampus

  2011cited by this paper
• Human TH17 Cells Are Long-Lived Effector Memory Cells

  2011cited by this paper
• The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity.

  2010cited by this paper
• Decoding cell death signals in inflammation and immunity.

  2010cited by this paper
• Adoptive cell transfer: a clinical path to effective cancer immunotherapy

  2008cited by this paper
• Inhibitory B7-family molecules in the tumour microenvironment

  2008cited by this paper
• UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development

  2007cited by this paper
• Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells.

  2007cited by this paper
• Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome

  2006cited by this paper
• B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma

  2006cited by this paper
• Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival

  2004cited by this paper
• The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3.

  2004cited by this paper
• Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity

  2003cited by this paper
• Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.

  2003cited by this paper
• Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells

  2001cited by this paper
• Time‐Dependent ROC Curves for Censored Survival Data and a Diagnostic Marker

  2000cited by this paper
• Development of a syngeneic mouse model for events related to ovarian cancer.

  2000cited by this paper
• Checking the Cox model with cumulative sums of martingale-based residuals

  1993cited by this paper

• Bibliometric analysis of ovarian cancer immune evasion research from 2015 to 2024

  2026cites this paper
• Cancer-Immunity Cycle-Based Smart Nucleic Acid Nanodrugs for Potentiated Immunotherapy

  2026cites this paper
• Pharmacological strategies to overcome immune checkpoint inhibitor resistance in non-small cell lung cancer

  2026cites this paper
• Bioinformatic analysis and cellular functional assays uncover the role of NXPH4 in breast cancer.

  2026cites this paper
• Chemokine CCL5 overexpression combined with radiotherapy modulates Th1-mediated immune response and leads to significant tumor growth delay in mouse tumor models.

  2026cites this paper
• Targeting cellular source-specific CXCL9 signaling for immunotherapy in oral squamous cell carcinoma.

  2026cites this paper
• Targeting epigenetic methylation: emerging diagnosis and therapeutic strategies in cancer

  2026cites this paper
• Modeling tumor progression in heterogeneous microenvironments: A cellular automata approach.

  2026cites this paper
• Targeting epigenetic regulators to boost T cell immunotherapy against cancer

  2026cites this paper
• Epigenetic modulation to overcome immune suppression in pancreatic cancer.

  2026cites this paper
• Combination Immunotherapy as a Promising Strategy to Overcome Immunotherapy Resistance: From Emergence to Next-Generation Approaches.

  2026cites this paper
• Co-delivery of chemokine CXCL9 and costimulatory ligand TNFSF9 by mesenchymal stem cells reprograms the immune microenvironment for triple-negative breast cancer

  2026cites this paper
• The power and the promise of epigenetic drugs in oncology

  2026cites this paper
• NIR-II Multimodal Phototheranostics Synergized with Antigen-Specific Vaccines for Boosted Cancer Photoimmunotherapy.

  2026cites this paper
• Epigenetic Regulation of Stromal and Immune Cells and Therapeutic Targets in the Tumor Microenvironment

  2025influential citation
• Expanding the immunotherapy universe in extensive-stage small cell lung cancer: from chemoimmunotherapy backbone to next-wave combinations

  2025cites this paper
• Post-translational modifications of proteins: dynamic regulatory network and therapeutic targets of tumor immune escape in pan-cancer.

  2025cites this paper
• KRTCAP2 is a prognostic biomarker associated with immune infiltration in kidney renal clear cell carcinoma

  2025cites this paper
• Genetic and Epigenetic Indicators Predicting Response to Immune Checkpoint Inhibitors

  2025cites this paper
• LD-110, a potent LSD1 PROTAC degrader, suppresses tumor growth by inducing ER stress and apoptosis.

  2025cites this paper
• Persistent IFN-γ signaling in acquired resistance to PD-(L)1 blockade in NSCLC

  2025cites this paper
• Epigenetic orchestration of cancer-immune dynamics: mechanisms, technologies, and clinical advancements.

  2025cites this paper
• Extranodal NK/T-cell lymphoma: an update of the molecular characterization of the tumor and microenvironment, and its clinical implications

  2025cites this paper
• Epigenetic Regulation of Immune Responses in Endocrine-Related Cancers and Its Role in Immunotherapy

  2025cites this paper
• Aging alters tumor cell - T cell crosstalk to promote breast cancer progression

  2025cites this paper
• Integrative and deep learning-based prediction of therapy response in ovarian cancer

  2025cites this paper
• Epigenetische Therapien in der Krebsbehandlung: Chancen und Herausforderungen

  2025cites this paper
• CRISPR screens define unified hallmarks of cancer cell-autonomous immune evasion.

  2025cites this paper
• A Spatiotemporal Model of CXCL10 as a Master Regulator of Immune Evasion and Metastasis in Osteosarcoma

  2025cites this paper
• Impaired ARID1A expression attenuated the immune response in gastric cancer via histone acetylation

  2025influential citation
• Treatment of NSCLC after chemoimmunotherapy — are we making headway?

  2025cites this paper
• Current strategies for armoring chimeric antigen receptor T-cells to overcome barriers of the solid tumor microenvironment

  2025cites this paper
• Mendelian randomization analysis of CpG methylation and immune phenotypes in epithelial ovarian cancer outcomes

  2025cites this paper
• Beyond Exosomes: An Ultrapurified Phospholipoproteic Complex (PLPC) as a Scalable Immunomodulatory Platform for Reprogramming Immune Suppression in Metastatic Cancer

  2025influential citation
• Steroids and One-Carbon Metabolism: Clinical Implications in Endocrine Disorders

  2025cites this paper
• DNMT1 reduces cisplatin sensitivity partially through downregulating FOXO3a in ovarian cancer cells.

  2025cites this paper
• The immune checkpoint regulator CD40 potentiates myocardial inflammation

  2025cites this paper
• The mechanism of EZH2/H3K27me3 downregulating CXCL10 to affect CD8+ T cell exhaustion to participate in the transformation from myelodysplastic syndrome to acute myeloid leukaemia

  2025cites this paper
• Inhibition of MBTPS1 enhances antitumor immunity and potentiates anti-PD-1 immunotherapy

  2025cites this paper
• Why combine and why neoadjuvant? Tumor immunological perspectives on chemoimmunotherapy in triple-negative breast cancer

  2025cites this paper
• The current and emerging immunotherapy paradigm in small-cell lung cancer

  2025cites this paper
• New Generation of Clinical Epigenetics Analysis and Diagnosis for Precision Medicine

  2025cites this paper
• TET2 has endothelial-specific roles in interferon responses that are dysregulated by hyperglycaemia in vitro and in vivo.

  2025cites this paper
• RNA Epigenetics in Cancer: Current Knowledge and Therapeutic Implications

  2025cites this paper
• Validation of CCL20-driven CAR-γδ T secreting PD-1 blockade with enhanced trafficking into solid tumor

  2025cites this paper
• The Critical Role of Homing in TIL Therapy Success: From Biology to Clinical Application.

  2025cites this paper
• Integrated analyses of prognostic and immunotherapeutic significance of EZH2 in uveal melanoma.

  2025cites this paper
• IFNγ-mediated suppression of alternative NF-κB in tumor-resident myeloid cells promotes selective recruitment of cytotoxic but not regulatory T cells

  2025cites this paper
• Turning cold tumors into hot tumors to ignite immunotherapy

  2025cites this paper
• Priming with DNMT Inhibitors Potentiates PD-1 Immunotherapy by Triggering Viral Mimicry in Relapsed/Refractory NK/T-cell Lymphoma

  2025cites this paper
• Exploring the role of EZH2 in neuroinflammation: implications for innovative therapeutic strategies

  2025cites this paper
• Synthetic lethality of EZH2 and DNMT Inhibition suppresses neuroblastoma proliferation via MYCN destabilization

  2025cites this paper
• Beyond tumour suppression: cGAS‐STING pathway in urologic malignancies: Context‐dependent duality and therapeutic implications

  2025cites this paper
• Prevention of cancer initiation by augmenting MHC-I antigen presentation via EZH2 inhibition

  2025cites this paper
• Development of DPP-4-resistant CXCL9-Fc and CXCL10-Fc chemokines for effective cancer immunotherapy

  2025cites this paper
• Epigenetic regulation of the tumor microenvironment in lung cancer: mechanism insights and therapeutic prospects

  2025cites this paper
• “Dissecting the role of T cell exhaustion in cancer progression: a multifaceted approach“

  2025cites this paper
• Ovarian Cancer Ascites Enriched for CCL23 Reduces Macrophage-Derived CXCL10 Secretion and Is Associated with Poor Patient Outcomes

  2025cites this paper
• Implications of EGFR expression on EGFR signaling dependency and adaptive immunity against EGFR-mutated lung adenocarcinoma.

  2025cites this paper
• Polycomb repressive complex 2 (PRC2) pathway’s role in cancer cell plasticity and drug resistance

  2025influential citation
• Epigenetic regulators combined with tumour immunotherapy: current status and perspectives

  2025cites this paper
• Glutamate promotes CCL2 expression to recruit tumor-associated macrophages by restraining EZH2-mediated histone methylation in hepatocellular carcinoma

  2025cites this paper
• EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models.

  2025cites this paper
• Immunomodulatory role of oncogenic alterations in non-small cell lung cancer: a review of implications for immunotherapy

  2025cites this paper
• The Role of the DNA Methyltransferase Family and the Therapeutic Potential of DNMT Inhibitors in Tumor Treatment

  2025influential citation
• Inhibition of histone methyltransferase EZH2 for immune interception of colorectal cancer in Lynch syndrome

  2025cites this paper
• H3K27me3-mediated regulation of PD-L1 expression in triple-negative breast cancer (TNBC).

  2025cites this paper
• CBX2 suppresses interferon signaling to diminish tumor immunogenicity via a noncanonical corepressor complex

  2025cites this paper
• Enhancer zeste homolog 2 (EZH2) targeting by small interfering RNA (siRNA); recent advances and prospect

  2025cites this paper
• Selected Elements of the Tumor Microenvironment (MMP-2, MMP-7, TIMP-2, CXCL-9, CXCL-10) in the Serum of Pediatric Patients with Acute Lymphoblastic Leukemia

  2025cites this paper
• The epigenetic hallmarks of immune cells in cancer

  2025cites this paper
• Revolutionary Cancer Therapy for Personalization and Improved Efficacy: Strategies to Overcome Resistance to Immune Checkpoint Inhibitor Therapy

  2025cites this paper
• The epigenetic basis of hepatocellular carcinoma – mechanisms and potential directions for biomarkers and therapeutics

  2025cites this paper
• Immunomodulation on tumor immune microenvironment in acquired targeted therapy resistance and implication for immunotherapy resistance

  2025cites this paper
• Regulation of immunogenic cell death and potential applications in cancer therapy

  2025cites this paper
• Immunogenomic cancer evolution: A framework to understand cancer immunosuppression.

  2025cites this paper
• The TRIB2-DNMT1 pathway generates an immune cold microenvironment in glioblastoma and its inhibition promotes immunotherapy.

  2025cites this paper
• NCOA3 impairs the efficacy of anti-PD-L1 therapy via HSP90α/EZH2/CXCL9 axis in colon cancer.

  2025cites this paper
• Checkpoint immunotherapy is associated with preferential activation of tumor antigen–specific CD4+ T cells in MDS

  2025cites this paper
• Evolving CAR T-Cell Therapy to Overcome the Barriers in Treating Pediatric Central Nervous System Tumors.

  2025cites this paper
• Reciprocal Modulation of Tumour and Immune Cell Motility: Uncovering Dynamic Interplays and Therapeutic Approaches

  2025cites this paper
• Mechanisms and Therapeutic Implications of EZH2 in Nasal Diseases

  2025cites this paper
• Phospholipid-Rich DC-Vesicles with Preserved Immune Fingerprints: A Stable and Scalable Platform for Precision Immunotherapy

  2025cites this paper
• Functional Characterization of Plasminogen Activator Urokinase as a Key Gene in Papillary Thyroid Carcinoma Lymph Node Metastasis

  2025cites this paper
• The roles of cell cycle proteins in regulating the tumor immune microenvironment

  2025cites this paper
• Targeting epigenetic reprogramming in DLBCL and its interaction with the tumor microenvironment for novel therapeutic approaches.

  2025cites this paper
• Research progress of adoptive tumor infiltrating lymphocyte therapy for cervical cancer

  2025cites this paper
• Immune Checkpoint Molecules in Hodgkin Lymphoma and Other Hematological Malignancies

  2025cites this paper
• STK25 Loss Augments Anti‐PD‐1 Therapy Efficacy by Regulating PD‐L1 Stability in Colorectal Cancer

  2025cites this paper
• Strategies to Overcome PD-1/PD-L1 Blockade Resistance: Focusing on Combination with Immune Checkpoint Blockades

  2025cites this paper
• Photo-triggered engineered microbes achieving dual epigenetic immunomodulation for gastric cancer.

  2025cites this paper
• EGFR: New Insights on Its Activation and Mutation in Tumor and Tumor Immunotherapy

  2025cites this paper
• ZEB1 promotes chemoimmunotherapy resistance in pancreatic cancer models by downregulating chromatin acetylation of CXCL16

  2025influential citation
• Gene Signature-Based Drug Screening Reveals Ponatinib Enhances Immunotherapy Efficacy in Triple-Negative Breast Cancer by Reversing MDSC-Mediated Immunosuppressive Tumor Microenvironment

  2025cites this paper
• Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma

  2025cites this paper
• Exploring novel strategies of oncolytic viruses and gut microbiota to enhance CAR-T cell therapy for colorectal cancer.

  2025cites this paper
• KMT2D deficiency potentiates antitumor immunity and sensitizes immune checkpoint blockade in urologic cancers

  2025cites this paper
• Overcoming resistance to anti-PD-L1 immunotherapy: mechanisms, combination strategies, and future directions

  2025cites this paper
• Pain - related methylation driver genes affect the prognosis of pancreatic cancer patients by altering immune function and perineural infiltration

  2025cites this paper
• EZH2 serves as a viable therapeutic target for myeloma-induced osteolytic bone destruction

  2025cites this paper