Epigenetic silencing of Th1 type chemokines shapes tumor immunity and immunotherapy

By D. Peng, Ilona Kryczek, N. Nagarsheth, Lili Zhao, Shuang Wei, Weimin Wang, Yuqing Sun, Ende Zhao, Linda Vatan, Wojciech Szeliga and 8 more. Nature, 2015

1,069 citations recorded by the source corpus.

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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/87474a01513cda237df9c4ffdb231290f638475e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Lieping Chen
2. J. Wolchok
3. W. Zou
4. Guido Kroemer
5. L. Zitvogel
6. C. June
7. George Coukos
8. Ilona Kryczek

Citations in the corpus

• Strength Model of Self-Regulation as Limited Resource: Assessment, Controversies, Update (2016, background): “Moreover, recent evidence suggests that an excess of blood glucose can serve as inviting fuel for pathogens, from bacterial infections to cancer (Peng et al., 2015; Rayfield et al., 1982).”
• Cold Tumors: A Therapeutic Challenge for Immunotherapy (2019, background): “DNMTi and Histone-lysine N-methyltransferase EZH2 inhibitors have also been shown to reverse epigenetic silencing of Th1-type chemokines in tumor cells, which is negatively associated with CD8 T cells in tumors and patient outcome (48).”
• Breast Cancer Immunotherapy: Facts and Hopes (2017, background): “Studies have shown epigenetic modulation can promote an type I interferon response and restore production of T helper type 1 cytokines and chemokines (68-69).”
• CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4 (2022, methodology): “Tumor volume was calculated as previously described (Peng et al., 2015).”