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Methylation of immune synapse genes modulates tumor immunogenicity
Anders Berglund, … , James Mulé, Sungjune Kim
Anders Berglund, … , James Mulé, Sungjune Kim
Published November 12, 2019
Citation Information: J Clin Invest. 2020;130(2):974-980. https://doi.org/10.1172/JCI131234.
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Concise Communication Immunology

Methylation of immune synapse genes modulates tumor immunogenicity

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Abstract

Cancer immune evasion is achieved through multiple layers of immune tolerance mechanisms including immune editing, recruitment of tolerogenic immune cells, and secretion of immunosuppressive cytokines. Recent success with immune checkpoint inhibitors in cancer immunotherapy suggests a dysfunctional immune synapse as a pivotal tolerogenic mechanism. Tumor cells express immune synapse proteins to suppress the immune system, which is often modulated by epigenetic mechanisms. When the methylation status of key immune synapse genes was interrogated, we observed disproportionately hypermethylated costimulatory genes and hypomethylation of immune checkpoint genes, which were negatively associated with functional T cell recruitment to the tumor microenvironment. Therefore, the methylation status of immune synapse genes reflects tumor immunogenicity and correlates with survival.

Authors

Anders Berglund, Matthew Mills, Ryan M. Putney, Imène Hamaidi, James Mulé, Sungjune Kim

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Figure 4

The methylation status of costimulatory ligands is prognostic in melanoma.

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The methylation status of costimulatory ligands is prognostic in melanom...
(A) Kaplan-Meier curves for DSS of melanoma patients with high, intermediate, and low tertiles of PC1 scores are shown. Higher PC1 scores represent hypermethylation of CSGs. (B) Box plot of PC1 score distribution based on melanoma patient staging. (C and D) Kaplan-Meier curves for DSS of UCEC patients with MSI (C) or without MSI (D) with high, intermediate, and low tertiles of PC1 scores are shown. (E) T cell recruitment in PC1High and PC1Low melanoma patients is approximated by gene expression of CD3E, CD4, and CD8B. (F) T effector functions in PC1High and PC1Low melanoma patients are approximated by gene expression of CD3ζ (CD247), granzyme B (GZMB), perforin (PRF1), and IFN-γ (IFNG). (G) Chemokines for immune cell trafficking in PC1High and PC1Low melanoma patients is approximated by gene expression of CCL2, CCL3, CCL4, CCL5, CCL9, and CCL10. (H) Immunogenicity of PC1High and PC1Low melanoma patients is approximated by gene expression of cGAS. P values in A, C, and D were derived from a log-rank test comparing PC1High and PC1Low groups. ****P < 0.0001 by 2-sided Student’s t test.

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