Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy

doi:10.1038/nature15520

. 2015 Nov 12;527(7577):249-53.

doi: 10.1038/nature15520. Epub 2015 Oct 26.

Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy

Dongjun Peng¹, Ilona Kryczek^{1

2}, Nisha Nagarsheth^{1

2}, Lili Zhao³, Shuang Wei¹, Weimin Wang¹, Yuqing Sun⁴, Ende Zhao¹, Linda Vatan¹, Wojciech Szeliga¹, Jan Kotarski⁵, Rafał Tarkowski⁵, Yali Dou⁴, Kathleen Cho^{4

6}, Sharon Hensley-Alford⁷, Adnan Munkarah⁷, Rebecca Liu^{6

8}, Weiping Zou^{1

2

6

9}

Affiliations

¹ Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
² Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA.
³ Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
⁴ Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
⁵ The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland.
⁶ The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁷ Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202, USA.
⁸ Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
⁹ Graduate Program in Tumor Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.

PMID: 26503055
PMCID: PMC4779053
DOI: 10.1038/nature15520

Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy

Dongjun Peng et al. Nature. 2015.

. 2015 Nov 12;527(7577):249-53.

doi: 10.1038/nature15520. Epub 2015 Oct 26.

Authors

Affiliations

¹ Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
² Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA.
³ Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
⁴ Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
⁵ The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland.
⁶ The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁷ Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202, USA.
⁸ Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
⁹ Graduate Program in Tumor Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.

PMID: 26503055
PMCID: PMC4779053
DOI: 10.1038/nature15520

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interests.

Figures

**Extended Data Figure 1. Epigenetic reprogramming alters immunotherapy**
**a–c**, Effects of DZNep and 5-AZA dC on ID8 mouse ovarian cancer progression. The ID8 tumor bearing mice (C57BL/6) were treated with DZNep and 5-AZA dC. (a) Tumor growth was recorded by Bioluminescence imaging and quantified by calculating the total flux (photons per second). The representative images and tumor volume at day 24 are shown. Day 0: tumor inoculation. (b) Tumor-infiltrating CD8⁺ T cells were quantified by immunohistochemistry staining (IHC) and expressed as the mean ± SEM per high-power field. (c) Tumor CXCL9 mRNA was quantified by real-time PCR. (mean/SEM, n = 5 per group, * P < 0.05, Mann-Whitney Test as compared to the control group or the group treated with DZNep or 5-AZA dC). **d, e,** Effects of EPZ6438 and 5-AZA dC on ID8 mouse ovarian cancer progression. The ID8 tumor bearing mice (C57BL/6) were treated with EPZ6438 and 5-AZA dC. (d) Tumor growth was recorded by Bioluminescence imaging and quantified by calculating the total flux (photons per second). The representative images and tumor volume at day 22 are shown. Day 0: tumor inoculation. (mean/SEM, * P < 0.05, One-way ANOVA). (e) Tumor CXCL9 mRNA was quantified by real-time PCR. (mean/SEM, * P < 0.05, One-way ANOVA). f, Effects of DZNep and 5-AZA dC on ovarian tumor progression in NOD-scid/IL-2Rγnull (NSG) mouse. Mouse ID8-luc ovarian cancer cells were intraperitoneally inoculated into NSG mice. Tumor-bearing mice were treated with DZNep and 5-AZA dC. Tumor growth was recorded and quantified by Bioluminescence imaging. The representative bioluminescence images on day 15 (days after tumor inoculation) are shown. n = 4 per group. (mean/SEM). **g–i,** Effects of DZNep and 5-AZA dC on anti-PD-L1 immunotherapy. Anti-PD-L1 (10mg/kg) was given to ID8 tumor bearing mice (C57BL/6) with or without DZNep and 5-AZA dC (5-Aza). (g) Tumor growth was recorded. The representative images and tumor volume at day 18 are shown. (h) Tumor-infiltrating CD8⁺ T cells were assessed and expressed as the mean ± SEM per high-power field. (i) Tumor CXCL9 gene expression was quantified and expressed as the mean values ± SEM. (n = 5 per group, *P < 0.05, Mann-Whitney Test) **j–l,** Effects of DZNep and 5-AZA dC on T cell immunotherapy. Autologous human tumor-specific human CD8⁺ T cells were transfused into ovarian cancer-bearing NOD-scid IL2Rγc null (NSG) mice with or without DZNep and 5-AZA dC treatment. The mice were treated with anti-CXCR3. Tumor volume was monitored (j). Th1-type chemokine expression was quantified by real-time PCR (k). Tumor-infiltrating T cells (l) were determined by FACS. (mean/SEM, n = 5 per group, * P < 0.05 Mann-Whitney Test). **m–q**, Effects of GSK126 and 5-AZA dC on T cell immunotherapy. Ovarian cancer-bearing NSG mice were treated with or without GSK126 and 5-AZA dC, and received autologous human ovarian cancer-specific CD8⁺ T cell transfusion. Tumor volume (m), tumor-infiltrating T cells (n) and T cell cytokine profile (**o–q**) were shown (mean/SEM, n = 5 per group, * P < 0.05 Mann-Whitney Test). Total tumor-infiltrating CD8⁺ T cells were normalized to the tumor volume (absolute number of CD8⁺ T cells/mm³ of the tumor). T cell cytokine profile was determined by FACS via gating on human CD45⁺CD8⁺ cells in tumor tissues. The percentages of TNFα⁺ and IFNγ⁺ cells are shown in CD8⁺ cells. Circle represents each mouse from the group. One of two experiments is shown. **r–t**, Effects of anti-CXCR3 on T cell survival. Tumor-specific human CD8⁺ T cells were transfused into NSG mice. The mice were treated with anti-CXCR3. Peripheral blood Annexin V⁺CD8⁺ human T cells (mean/SEM, n = 5 per group) (**r, s**) and spleen CXCR3⁺CD8⁺ human T cells (t) were determined by FACS.

**Extended Data Figure 2. EZH2 controls Th1-type chemokines**
a, Effect of DZNep on CXCL10 transcript expression. Primary ovarian cancer cells were treated with DZNep in the presence of IFNγ for different time (hours). CXCL10 gene expression was quantified by real-time PCR. One of three experiments is shown. **b, c,** Effects of DZNep on ovarian cancer Th1-type chemokine expression. Human primary ovarian cancer cells were treated for 24 (b) or 48 (c) hours with DZNep in the presence of IFNγ. CXCL9 and CXCL10 expression were quantified by real-time PCR (b) or detected by ELISA (c). (mean/SEM, n = 5, * P < 0.05, Wilcoxon test) d, Effects of DZNep on IFNGR2 transcript expression. Primary ovarian cancer cells were treated with DZNep in the presence of IFNγ for 24 hours. IFNGR2 expression was quantified by real-time PCR. One of 3 experiments is shown. e, Effects of histone methyltransferase G9a/GLP inhibitors on Th1-type chemokine expression. Primary ovarian cancer cells were treated with BIX01294 or UNC0638 in the presence of IFNγ for 24 hours. CXCL10 gene expression was quantified by real-time PCR. One of 3 experiments is shown. f, Effects of DZNep on the expression of EZH2 and H3K27me3. Primary ovarian cancer cells were treated with or without DZNep for 24 hours. The levels of EZH2, H3K27me3 were detected by Western blotting. One of 3 experiments is shown. **g, h**, Effects of EPZ6438 on histone marks (g) and CXCL9 mRNA expression (h). Mouse ID8 ovarian cancer cells were treated with EPZ6438 in the presence or absence of IFNg for 48 hours. H3K27me3 and H3K9me2 were detected by Western blotting. CXCL9 transcripts were quantified by real-time PCR. (Mean/SEM, 4 repeats, * P < 0.05, Wilcoxon test) i, EZH2 knockdown in primary ovarian cancer cells mediated by EZH2 shRNA. Primary ovarian cancer cells were stably transduced with a lentiviral shRNA expressing vector (non-target shRNA (Ctl) or EZH2 shRNA, shEZH2). The levels of EZH2 and H3K27me3 were detected by Western Blotting. **j, k**, Effects of EZH2 knockdown on IFNGR2 and HLA-B gene expression. Primary ovarian cancer cells were stably transduced with non-target shRNA (Ctl) or EZH2 shRNA (shEZH2). IFNGR2 (j) and HLA-B (k) gene expression were quantified by real-time PCR. (mean/SEM, n = 4) **l, m,** Effect of DZNep on H3K27me3 occupancy at Th1-type chemokine promoters. H3K27me3 ChIP assay was performed in primary ovarian cancer cells treated with DZNep with or without IFNγ. H3K27me3 levels at the gene promoter of CXCL9 and CXCL10 were normalized to the input. (mean/SEM, n = 5, * P < 0.05, Wilcoxon test) n, Effects of EZH2 knockdown on H3K27me3 occupancy at the HOXB1 gene promoter. H3K27me3 ChIP assay was performed in shEZH2 or non-target shRNA expressing primary ovarian cancer cells. H3K27me3 levels at the gene promoter of HOXB1 were normalized to the input. (mean/SEM, n = 5, * P < 0.05, Wilcoxon test)

**Extended Data Figure 3. H3K27-specific methyltransferase and demethylase regulates Th1-type chemokine expression**
a, Effects of GSK126 treatment on H3K27me3. Primary ovarian cancer cells were treated with GSK126 (0, 0.05, 0.2, 0.5, 2 and 10 μM) for 48 hours. H3K27me3 was detected by Western Blotting. One of 3 experiments is shown. **b, c**, Effects of GSK126 on EZH2 and IFNGR2 transcripts expression. Primary ovarian cancer cells were pretreated with GSK126 for 48 hours and stimulated with IFNγ for additional 24 hours. EZH2 (b) and IFNGR2 (c) transcripts were quantified by real-time PCR. Results are expressed as the mean ± SEM. 3 experiments with duplicates. d, Effects of GSK126 on cell apoptosis. Primary ovarian cancer cells were treated with GSK126 and stained with PI and Annexin-V. The percentage of apoptotic cells (Annexin-V positive) was quantified. mean/SEM in 3 experiments with duplicates. **e–h**, Effects of histone methyltransferase inhibitors on ovarian cancer Th1-type chemokine expression. Human primary ovarian cancer cells (OC17) (e), or ovarian cancer cell lines (ES-2, CAOV3 and A2780) (**f–h**) were treated with GSK126 with or without IFNγ. CXCL9 and CXCL10 expression was measured by ELISA (e) or real-time PCR (**f–h**). (mean/SEM, n = 5, * P < 0.05, Wilcoxon test) i, Effects of ectopic JMJD3 on histone marks. Primary ovarian cancer cells were transiently transfected with plasmid encoding HA-JMJD3. Histone markers H3K9me2, H3K9me3 and H3K27me3 were detected by Western Blotting. One of 3 experiments is shown. j, Effect of ectopic expression of JMJD3 on CXCL10 transcripts expression. Primary ovarian cancer cells were transiently transfected with vector or different amounts of HA-JMJD3 plasmids and stimulated with IFNγ. CXCL10 transcripts were quantified by real-time PCR. Results are expressed as the mean values ± SEM. Data represent 3 independent experiments. (n = 5, * P < 0.05, Wilcoxon test) **k, l**, Effects of ectopic JMJD3 on IFNGR2 (k) and HLA-B (l) gene expression. Primary ovarian cancer cells were transiently transfected with plasmid encoding HA-JMJD3 and stimulated with IFNγ. IFNGR2 and HLA-B transcripts were quantified by real-time PCR. Results are expressed as the mean relative ± SEM. Data represent 3 independent experiments. m, Effects of JMJD3 knockdown on IFNGR2 gene expression. Primary ovarian cancer cells were stably transduced with a lentiviral shRNA specific for JMJD3 (shJMJD3) or non-target shRNA (Ctl), and stimulated with IFNγ. IFNGR2 transcripts were quantified by real-time PCR. Results are expressed as the mean values ± SEM. Data represent 3 independent experiments. n, Effects of GSK-J4 on histone marks. Primary ovarian cancer cells were treated with GSK-J4 (10 μM) for 48 hours. H3K27me3, H3K4me1, H3K4me2 and H3K4me3 were detected by Western Blotting. One of 3 experiments is shown. o, Effects of GSK-J4 on IFNGR2 gene expression. Primary ovarian cancer cells were pretreated with GSK-J4 (10 μM) for 48 hours and stimulated with IFNγ for additional 24 hours. IFNGR2 transcripts were quantified by real-time PCR. Results are expressed as the mean values ± SEM. Data represent 3 independent experiments.

**Extended Data Figure 4. DNA methylation controls Th1-type chemokine expression**
**a, b,** Effects of 5-AZA dC on Th1-type chemokine expression. Human ovarian cancer cell line (A2780) or primary ovarian cancer cells (OC17) were treated with 5-AZA dC and IFNγ. CXCL9 and CXCL10 expression were quantified by real-time PCR (a) or ELISA (b). (mean/SEM, n = 6, * P < 0.05, Wilcoxon test) **c–f**, Effects of 5-Aza dC on IFNγ associated gene expression. Primary ovarian cancer cells (OC8) were treated with 5-AZA dC and IFNγ for 24 hours. CXCL9 (c), CXCL10 (d), IRF1 (e) and IFNGR2 (f) transcripts were quantified by real-time PCR. Results are expressed as the mean values ± SEM. One of 3 independent experiments is shown. g, DNMT1 knockdown via DNMT1 shRNA. Primary ovarian cancer cells (OC8) were transduced with a lentiviral shRNA specific for DNMT1 (shDNMT1) or non-target shRNA (Ctl). DNMT1 was detected by Western Blotting. h, Effect of DNMT1 knockdown on IFNGR2 expression. Primary ovarian cancer cells (OC8) were transduced with a lentiviral shRNA specific for DNMT1 (shDNMT1) or non-target shRNA (Ctl) and stimulated with IFNγ for 24 hours. IFNGR2 transcripts were quantified by real-time PCR. Results are expressed as the mean values ± SEM. Data represent 3 independent experiments. i, STAT1 binding site at CXC10 gene promoter. STAT1 ChIP-seq dataset from ENCODE/SYDH (Top panel). K562 cells were treated with IFNγ for 30 minutes or 6 hours. Non-treated GM12878 cells were used as control (no IFNγ). GEO accession #: GSM935487, GSM935488 and GSM935612. STAT1 occupancy at CXCL10 promoter (−5143 to −4699) is shown as the peaks. Middle panel, schematic diagram of CXCL10 gene locus. STAT1-binding site (TTCCCGGAA) were predicted by TFSEARCH, score = 100. STAT1 ChIP-seq peaks overlap with the predicted STAT1-binding site (indicated as vertical lines). Bottom, homologous STAT1 binding site at CXCL10 gene promoter (Ensemble Genomic alignment).

**Extended Data Figure 5. EZH2/H3K27 and DNMT1 interaction affects clinical outcome**
**a–b,** Representative images of immunohistochemistry staining of EZH2 (a) and DNMT1 (b) in human ovarian cancer tissues. The levels of DNMT1 and EZH2 expression in the tumor were assessed by H-score method. **c–d,** The association between EZH2 (c), DNMT1 (d) and patient disease free survival in high-grade serous ovarian cancer. The high and low levels of EZH2 and DNMT1 were determined by the median values (see Extended Data Table 1). e, Relative impact of EZH2, DNMT1 and CD8 on patient disease free survival in high-grade serous ovarian cancer. The time-dependent receiver operating characteristic (ROC) curve analysis was applied to evaluate the predictive accuracy of each marker for disease free survival. AUC, the area under the ROC curve. (T = 60). f, Impact of the two parameters (EZH2 and DNMT1) on patient disease free survival. The analysis was performed on patients with high-grade serous ovarian cancer. Multiple comparisons were performed in long-rank test. EZH2^lowDNMT1^low group (n = 49) vs EZH2^highDNMT1^high (n = 55) P < 0.00001. g, Representative images of immunohistochemistry staining of CD8 in human ovarian cancer specimen. Intratumoral CD8⁺ T cells were shown with anti-CD8⁺ staining. The numbers of intratumoral CD8⁺ T cells were quantified in high power fields (40X). (See Methods and Extended Data Table 1). h, The relationship between intratumoral CD8⁺ T cells and patient disease free survival in high-grade serous ovarian cancer. (See Methods and Extended Data Table 1). i, Schematic diagram depicting the relationship among epigenetic Th1-type chemokine silencing, effector T cell trafficking, and tumor immunity, immunotherapy and patient outcome.

**Figure 1. Epigenetic reprogramming alters cancer T cell immunotherapy**
Effects of GSK126 and 5-AZA dC on T cell immunotherapy. Ovarian cancer-bearing NSG mice were treated with GSK126, 5-AZA dC and/or anti-CXCR3, and received TAA-specific CD8⁺ T cell transfusion. Tumor volume (a), tumor chemokine expression (**b, c**), tumor-infiltrating T cells and blood T cells (**d, e**) were shown. CXCL10 transcript was quantified in tumor and immune cells from tumor tissues in NSG model (f). Tumor and immune cells (10⁶/ml) were isolated from ovarian cancer from patients, and were treated for 48 hours in the indicated conditions. CXCL10 protein was measured by ELISA (g) (mean/SD, n = 5, * P < 0.05, Mann-Whitney Test).

**Figure 2. Histone methyltransferase represses Th1-type chemokines**
**a, b**, Effects of EZH2 knockdown on cancer Th1-type chemokine expression. shEZH2 and control vector expressing primary ovarian cancer cells were stimulated with IFNγ, and chemokines were quantified by real-time PCR (a) or ELISA (b). (mean/SD, n = 6, * P < 0.05, Wilcoxon test) c, Effect of shEZH2 on H3K27me3 occupancy at Th1-type chemokine promoters. H3K27me3 ChIP was performed in shEZH2 expressing primary ovarian cancer cells. H3K27me3 levels at the gene promoter of CXCL9 and CXCL10 were normalized to the input. (mean/SD, n = 5, * P < 0.05, Wilcoxon test) d, Effects of GSK126 on cancer Th1-type chemokine expression. Primary ovarian cancer cells were pretreated with GSK126 and stimulated with IFNγ for 24 hours. Chemokine transcripts were quantified by real-time PCR. (mean/SEM, n = 6, * P < 0.05, Wilcoxon test) **e–g,** Effects of JMJD3 on cancer Th1-type chemokine expression. Primary ovarian cancer cells were transfected with plasmids encoding HA-JMJD3 (e), or with a lentiviral shJMJD expressing vector (f) or pretreated with GSK-J4 (g), and stimulated with IFNγ for 24 hours. Chemokine transcripts were quantified by real-time PCR. (mean/SD, n = 5, *P < 0.05, Wilcoxon test) h, Effects of EZH2 and H3K27me3 manipulation on global changes of gene expression. Primary ovarian cancer cells were treated with GSK126, or transduced with a shEZH2 lentivirus, and stimulated with IFNγ. Heat map shows differential up-regulation and down-regulation of genes in GSK126 treated cells and in shEZH2 cells compared to the controls. The 20 overlapped differentially expressed genes in both shEZH2 and GSK126 treated cells were shown on the top. Two repeats/condition.

**Figure 3. DNA methylation regulates Th1-type chemokine expression**
**a–c**, Effects of 5-AZA dC on Th1-type chemokine expression. Primary ovarian cancer cells were treated with 5-AZA dC and IFNγ for 24 (**a, b**) or 48 hours (c). CXCL9 and CXCL10 transcripts (**a, b**) and protein (c) were quantified by real-time PCR or ELISA. (mean/SD, n = 7, * P < 0.05, Wilcoxon test) **d–f**, Effects of shDNMT1 on Th1-type chemokine expression. Primary ovarian cancer cells were transduced with shDNMT1 or non-target shRNA and stimulated with IFNγ. Chemokine transcript (**d, e**) and protein (f) were quantified by real-time PCR and ELISA. (mean/SEM, n = 5, * P < 0.05, Wilcoxon test) g, Effects of 5-AZA dC on DNA methylation on the promoter of CXCL10 gene. Schematic diagram of *CXCL10* gene locus is shown (Top). Primary ovarian cancer cells were treated with 5-AZA dC. DNA methylation at CpG sites was quantified by bisulfite sequencing. Results are shown as the percentage of methylation. Filled circle, methylated; open circle, unmethylated. The arrows indicate the locations of primers.

**Figure 4. EZH2/H3K27 and DNMT1 interaction and its impact on clinical outcome**
a, Effects of GSK126 and 5-AZA dC on H3K27me3 and DNMT1. Primary ovarian cancer cells were treated with GSK126 or/and 5-AZA dC for 48 hours. Histone marks and DNMT1 were detected by Western Blotting. **b, c, d** Effects of 5-AZA dC and GSK126 on tumor CXCL10. shEZH2 (b), shDNMT1 (c) and primary (d) ovarian cancer cells were treated with 5-AZA dC for 2 days (**b, c**) or with DZNep and/or 5-AZA dC for 3 days (d), followed by IFNγ stimulation. CXCL10 was quantified by real-time PCR (**b, c**) and ELISA (d). (mean/SEM, n = 5–6, * P < 0.05, Wilcoxon test) **e, f,** The association between EZH2 (e), DNMT1 (f) and OS. P < 0.0001. g, Impact of EZH2, DNMT1 and CD8⁺ T cells on OS. The ROC curve analysis was applied to evaluate the predictive accuracy of each marker for OS. (T = 60) h, Impact of EZH2 and DNMT1 on OS. EZH2^lowDNMT1^low **(n = 50)**, EZH2^highDNMT1^high **(n = 57)**, EZH2^lowDNMT1^high, and EZH2^highDNMT1^low **(n = 66)** were compared. Long-rank test, P < 0.0001, EZH2^lowDNMT1^low vs EZH2^highDNMT1^high. i, The relationship between intratumoral CD8⁺ T cells and OS. P < 0.0001. **j, k, l,** The Pearson correlation between intratumoral CD8⁺ T cells and EZH2 (n = 169, r = −0.24, P = 0.002) (j) and DNMT1 (n = 170, r = −0.28, P = 0.0003) (k) and the accumulating levels of EZH2 and DNMT1 (n = 168, r = −0.32, P < 0.0001) (l).

See this image and copyright information in PMC

Comment in

Tumour immunology: Reducing silence to improve therapy.
Kugelberg E. Kugelberg E. Nat Rev Immunol. 2015 Dec;15(12):730. doi: 10.1038/nri3941. Epub 2015 Nov 6. Nat Rev Immunol. 2015. PMID: 26542634 No abstract available.

Cited by

The Dual Role of STAT1 in Ovarian Cancer: Insight Into Molecular Mechanisms and Application Potentials.
Li X, Wang F, Xu X, Zhang J, Xu G. Li X, et al. Front Cell Dev Biol. 2021 Mar 23;9:636595. doi: 10.3389/fcell.2021.636595. eCollection 2021. Front Cell Dev Biol. 2021. PMID: 33834023 Free PMC article. Review.
A Randomized Phase II Trial Comparing the Efficacy and Safety of Pioglitazone, Clarithromycin and Metronomic Low-Dose Chemotherapy with Single-Agent Nivolumab Therapy in Patients with Advanced Non-small Cell Lung Cancer Treated in Second or Further Line (ModuLung).
Heudobler D, Schulz C, Fischer JR, Staib P, Wehler T, Südhoff T, Schichtl T, Wilke J, Hahn J, Lüke F, Vogelhuber M, Klobuch S, Pukrop T, Herr W, Held S, Beckers K, Bouche G, Reichle A. Heudobler D, et al. Front Pharmacol. 2021 Mar 16;12:599598. doi: 10.3389/fphar.2021.599598. eCollection 2021. Front Pharmacol. 2021. PMID: 33796020 Free PMC article.
Molecular subtypes identified by pyroptosis-related genes are associated with tumor microenvironment cell infiltration in colon cancer.
Ling Y, Wang Y, Cao C, Feng L, Zhang B, Li S. Ling Y, et al. Aging (Albany NY). 2022 Nov 16;14(22):9020-9036. doi: 10.18632/aging.204379. Epub 2022 Nov 16. Aging (Albany NY). 2022. PMID: 36384889 Free PMC article.
Turning cold tumors into hot tumors by improving T-cell infiltration.
Liu YT, Sun ZJ. Liu YT, et al. Theranostics. 2021 Mar 11;11(11):5365-5386. doi: 10.7150/thno.58390. eCollection 2021. Theranostics. 2021. PMID: 33859752 Free PMC article. Review.
PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity.
Kim H, Kim H, Feng Y, Li Y, Tamiya H, Tocci S, Ronai ZA. Kim H, et al. Sci Transl Med. 2020 Jul 8;12(551):eaaz5683. doi: 10.1126/scitranslmed.aaz5683. Sci Transl Med. 2020. PMID: 32641491 Free PMC article.

See all "Cited by" articles

References

1. Timp W, Feinberg AP. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nature reviews. Cancer. 2013;13:497–510. doi: 10.1038/nrc3486nrc3486. [pii] - DOI - PMC - PubMed
1. Curiel TJ, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003;9:562–567. - PubMed
1. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467–477. - PubMed
1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews. Cancer. 2012;12:252–264. doi: 10.1038/nrc3239nrc3239. [pii] - DOI - PMC - PubMed
1. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nature reviews Cancer. 2008;8:299–308. - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases
Research Materials
- Addgene Non-profit plasmid repository
- NCI CPTC Antibody Characterization Program

[1] Timp W, Feinberg AP. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nature reviews. Cancer. 2013;13:497–510. doi: 10.1038/nrc3486nrc3486. [pii] - DOI - PMC - PubMed

[2] Timp W, Feinberg AP. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nature reviews. Cancer. 2013;13:497–510. doi: 10.1038/nrc3486nrc3486. [pii] - DOI - PMC - PubMed

[3] Curiel TJ, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003;9:562–567. - PubMed

[4] Curiel TJ, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003;9:562–567. - PubMed

[5] Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467–477. - PubMed

[6] Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467–477. - PubMed

[7] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews. Cancer. 2012;12:252–264. doi: 10.1038/nrc3239nrc3239. [pii] - DOI - PMC - PubMed

[8] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews. Cancer. 2012;12:252–264. doi: 10.1038/nrc3239nrc3239. [pii] - DOI - PMC - PubMed

[9] Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nature reviews Cancer. 2008;8:299–308. - PMC - PubMed

[10] Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nature reviews Cancer. 2008;8:299–308. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy

Affiliations

Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Research Materials

Abstract

Conflict of interest statement

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Research Materials