PRC2-Mediated Epigenetic Suppression of Type I IFN-STAT2 Signaling Impairs Antitumor Immunity in Luminal Breast Cancer

Overview

Journal Cancer Res

Specialty Oncology

Date 2022 Oct 12

PMID 36222718

Authors

Juyeong Hong

Ji Hoon Lee

Zhao Zhang

Yanming Wu

Mei Yang

Yiji Liao

Richard de la Rosa

Jessica Scheirer

Douglas Pechacek

Nu Zhang

Zhenming Xu

Tyler Curiel

Xi Tan

Tim H-M Huang

Kexin Xu

Affiliations

Soon will be listed here.

Abstract

Significance: Inhibition of EZH2 activates a type I IFN-STAT2 signaling axis and provides a therapeutic strategy to stimulate antitumor immunity and therapy responsiveness in immunologically cold luminal breast cancer.

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References

Kareva I . Metabolism and Gut Microbiota in Cancer Immunoediting, CD8/Treg Ratios, Immune Cell Homeostasis, and Cancer (Immuno)Therapy: Concise Review. Stem Cells. 2019; 37(10):1273-1280. DOI: 10.1002/stem.3051. View

Gibney G, Weiner L, Atkins M . Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016; 17(12):e542-e551. PMC: 5702534. DOI: 10.1016/S1470-2045(16)30406-5. View

Chen K, Liu J, Cao X . Regulation of type I interferon signaling in immunity and inflammation: A comprehensive review. J Autoimmun. 2017; 83:1-11. DOI: 10.1016/j.jaut.2017.03.008. View

Knutson S, Warholic N, Wigle T, Klaus C, Allain C, Raimondi A . Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013; 110(19):7922-7. PMC: 3651445. DOI: 10.1073/pnas.1303800110. View

Dai E, Zhu Z, Wahed S, Qu Z, Storkus W, Guo Z . Epigenetic modulation of antitumor immunity for improved cancer immunotherapy. Mol Cancer. 2021; 20(1):171. PMC: 8691037. DOI: 10.1186/s12943-021-01464-x. View

deLeeuw R, Kost S, Kakal J, Nelson B . The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res. 2012; 18(11):3022-9. DOI: 10.1158/1078-0432.CCR-11-3216. View

Morel K, Sheahan A, Burkhart D, Baca S, Boufaied N, Liu Y . EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer. Nat Cancer. 2021; 2(4):444-456. PMC: 8061902. DOI: 10.1038/s43018-021-00185-w. View

Beguelin W, Popovic R, Teater M, Jiang Y, Bunting K, Rosen M . EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013; 23(5):677-92. PMC: 3681809. DOI: 10.1016/j.ccr.2013.04.011. View

Hu Q, Nonaka K, Wakiyama H, Miyashita Y, Fujimoto Y, Jogo T . Cytolytic activity score as a biomarker for antitumor immunity and clinical outcome in patients with gastric cancer. Cancer Med. 2021; 10(9):3129-3138. PMC: 8085935. DOI: 10.1002/cam4.3828. View

10.

Sarkis P, Ying S, Xu R, Yu X . STAT1-independent cell type-specific regulation of antiviral APOBEC3G by IFN-alpha. J Immunol. 2006; 177(7):4530-40. DOI: 10.4049/jimmunol.177.7.4530. View

11.

Cao Q, Wang X, Zhao M, Yang R, Malik R, Qiao Y . The central role of EED in the orchestration of polycomb group complexes. Nat Commun. 2014; 5:3127. PMC: 4073494. DOI: 10.1038/ncomms4127. View

12.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

13.

Nagarsheth N, Peng D, Kryczek I, Wu K, Li W, Zhao E . PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer. Cancer Res. 2015; 76(2):275-82. PMC: 4715964. DOI: 10.1158/0008-5472.CAN-15-1938. View

14.

Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman D . IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017; 127(8):2930-2940. PMC: 5531419. DOI: 10.1172/JCI91190. View

15.

Langmead B, Trapnell C, Pop M, Salzberg S . Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009; 10(3):R25. PMC: 2690996. DOI: 10.1186/gb-2009-10-3-r25. View

16.

Fu X, De Angelis C, Schiff R . Interferon Signaling in Estrogen Receptor-positive Breast Cancer: A Revitalized Topic. Endocrinology. 2021; 163(1). DOI: 10.1210/endocr/bqab235. View

17.

Padovan E, Spagnoli G, Ferrantini M, Heberer M . IFN-alpha2a induces IP-10/CXCL10 and MIG/CXCL9 production in monocyte-derived dendritic cells and enhances their capacity to attract and stimulate CD8+ effector T cells. J Leukoc Biol. 2002; 71(4):669-76. View

18.

Wakiyama H, Masuda T, Motomura Y, Hu Q, Tobo T, Eguchi H . Cytolytic Activity (CYT) Score Is a Prognostic Biomarker Reflecting Host Immune Status in Hepatocellular Carcinoma (HCC). Anticancer Res. 2018; 38(12):6631-6638. DOI: 10.21873/anticanres.13030. View

19.

Selinger E, Reinis M . Epigenetic View on Interferon γ Signalling in Tumour Cells. Folia Biol (Praha). 2019; 64(4):125-136. DOI: 10.14712/fb2018064040125. View

20.

Robinson D, Wu Y, Lonigro R, Vats P, Cobain E, Everett J . Integrative clinical genomics of metastatic cancer. Nature. 2017; 548(7667):297-303. PMC: 5995337. DOI: 10.1038/nature23306. View