Distinct Epigenetic Features of Tumor-reactive CD8+ T Cells in Colorectal Cancer Patients Revealed by Genome-wide DNA Methylation Analysis

Overview

Journal Genome Biol

Specialties Biology
Genetics

Date 2020 Jan 2

PMID 31892342

Citations 63

Authors

Rui Yang

Sijin Cheng

Nan Luo

Ranran Gao

Kezhuo Yu

Boxi Kang

Li Wang

Qiming Zhang

Qiao Fang

Lei Zhang

Chen Li

Aibin He

Xueda Hu

Jirun Peng

Xianwen Ren

Zemin Zhang

Affiliations

Soon will be listed here.

Abstract

Background: Tumor-reactive CD8+ tumor-infiltrating lymphocytes (TILs) represent a subtype of T cells that can recognize and destroy tumor specifically. Understanding the regulatory mechanism of tumor-reactive CD8+ T cells has important therapeutic implications. Yet the DNA methylation status of this T cell subtype has not been elucidated.

Results: In this study, we segregate tumor-reactive and bystander CD8+ TILs, as well as naïve and effector memory CD8+ T cell subtypes as controls from colorectal cancer patients, to compare their transcriptome and methylome characteristics. Transcriptome profiling confirms previous conclusions that tumor-reactive TILs have an exhausted tissue-resident memory signature. Whole-genome methylation profiling identifies a distinct methylome pattern of tumor-reactive CD8+ T cells, with tumor-reactive markers CD39 and CD103 being specifically demethylated. In addition, dynamic changes are observed during the transition of naïve T cells into tumor-reactive CD8+ T cells. Transcription factor binding motif enrichment analysis identifies several immune-related transcription factors, including three exhaustion-related genes (NR4A1, BATF, and EGR2) and VDR, which potentially play an important regulatory role in tumor-reactive CD8+ T cells.

Conclusion: Our study supports the involvement of DNA methylation in shaping tumor-reactive and bystander CD8+ TILs, and provides a valuable resource for the development of novel DNA methylation markers and future therapeutics.

Citing Articles

Characterization of Rationally Designed CRISPR/Cas9-Based DNA Methyltransferases with Distinct Methyltransferase and Gene Silencing Activities in Human Cell Lines and Primary Human T Cells.

Guerra-Resendez R, Lydon S, Ma A, Bedford G, Reed D, Kim S ACS Synth Biol. 2025; 14(2):384-397.

PMID: 39898483 PMC: 11854388. DOI: 10.1021/acssynbio.4c00569.

Epigenetic Regulation of Stromal and Immune Cells and Therapeutic Targets in the Tumor Microenvironment.

Liu K, Li Y, Shen M, Xu W, Wu S, Yang X Biomolecules. 2025; 15(1).

PMID: 39858465 PMC: 11764280. DOI: 10.3390/biom15010071.

Tracing post-domestication historical events and screening pre-breeding germplasm from large gene pools in wheat in the absence of phenotype data.

Sertse D, Fetene A, Leon J, You F, Cloutier S, McCartney C Theor Appl Genet. 2024; 137(10):237.

PMID: 39340687 DOI: 10.1007/s00122-024-04738-2.

Single-cell and spatial transcriptome analyses reveal tertiary lymphoid structures linked to tumour progression and immunotherapy response in nasopharyngeal carcinoma.

Liu Y, Ye S, He S, Chi D, Wang X, Wen Y Nat Commun. 2024; 15(1):7713.

PMID: 39231979 PMC: 11375053. DOI: 10.1038/s41467-024-52153-4.

PARP enzymes and mono-ADP-ribosylation: advancing the connection from interferon-signalling to cancer biology.

Morone B, Grimaldi G Expert Rev Mol Med. 2024; 26:e17.

PMID: 39189367 PMC: 11440612. DOI: 10.1017/erm.2024.13.

References

Ronchetti S, Nocentini G, Riccardi C, Pandolfi P . Role of GITR in activation response of T lymphocytes. Blood. 2002; 100(1):350-2. DOI: 10.1182/blood-2001-12-0276. View

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

Intlekofer A, Takemoto N, Wherry E, Longworth S, Northrup J, Palanivel V . Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol. 2005; 6(12):1236-44. DOI: 10.1038/ni1268. View

Morita S, Noguchi H, Horii T, Nakabayashi K, Kimura M, Okamura K . Targeted DNA demethylation in vivo using dCas9-peptide repeat and scFv-TET1 catalytic domain fusions. Nat Biotechnol. 2016; 34(10):1060-1065. DOI: 10.1038/nbt.3658. View

Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q . Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med. 2010; 16(10):1147-51. PMC: 3326577. DOI: 10.1038/nm.2232. View

Kongsbak M, Levring T, Geisler C, von Essen M . The vitamin d receptor and T cell function. Front Immunol. 2013; 4:148. PMC: 3684798. DOI: 10.3389/fimmu.2013.00148. View

Philip M, Fairchild L, Sun L, Horste E, Camara S, Shakiba M . Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature. 2017; 545(7655):452-456. PMC: 5693219. DOI: 10.1038/nature22367. View

Haeussler M, Zweig A, Tyner C, Speir M, Rosenbloom K, Raney B . The UCSC Genome Browser database: 2019 update. Nucleic Acids Res. 2018; 47(D1):D853-D858. PMC: 6323953. DOI: 10.1093/nar/gky1095. View

Zheng C, Zheng L, Yoo J, Guo H, Zhang Y, Guo X . Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. Cell. 2017; 169(7):1342-1356.e16. DOI: 10.1016/j.cell.2017.05.035. View

10.

Pauken K, Sammons M, Odorizzi P, Manne S, Godec J, Khan O . Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science. 2016; 354(6316):1160-1165. PMC: 5484795. DOI: 10.1126/science.aaf2807. View

11.

Simoni Y, Becht E, Fehlings M, Loh C, Koo S, Teng K . Bystander CD8 T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature. 2018; 557(7706):575-579. DOI: 10.1038/s41586-018-0130-2. View

12.

Scott A, Dundar F, Zumbo P, Chandran S, Klebanoff C, Shakiba M . TOX is a critical regulator of tumour-specific T cell differentiation. Nature. 2019; 571(7764):270-274. PMC: 7698992. DOI: 10.1038/s41586-019-1324-y. View

13.

Pearce E, Mullen A, Martins G, Krawczyk C, Hutchins A, Zediak V . Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science. 2003; 302(5647):1041-3. DOI: 10.1126/science.1090148. View

14.

Kratchmarov R, Magun A, Reiner S . TCF1 expression marks self-renewing human CD8 T cells. Blood Adv. 2018; 2(14):1685-1690. PMC: 6058237. DOI: 10.1182/bloodadvances.2018016279. View

15.

Picelli S, Faridani O, Bjorklund A, Winberg G, Sagasser S, Sandberg R . Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc. 2014; 9(1):171-81. DOI: 10.1038/nprot.2014.006. View

16.

Williams J, Horton B, Zheng Y, Duan Y, Powell J, Gajewski T . The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment. J Exp Med. 2017; 214(2):381-400. PMC: 5294847. DOI: 10.1084/jem.20160485. View

17.

Yang R, Cheng S, Luo N, Gao R, Yu K, Kang B . Distinct epigenetic features of tumor-reactive CD8+ T cells in colorectal cancer patients revealed by genome-wide DNA methylation analysis. Genome Biol. 2020; 21(1):2. PMC: 6937914. DOI: 10.1186/s13059-019-1921-y. View

18.

Bonasio R, Tu S, Reinberg D . Molecular signals of epigenetic states. Science. 2010; 330(6004):612-6. PMC: 3772643. DOI: 10.1126/science.1191078. View

19.

Godec J, Cowley G, Barnitz R, Alkan O, Root D, Sharpe A . Inducible RNAi in vivo reveals that the transcription factor BATF is required to initiate but not maintain CD8+ T-cell effector differentiation. Proc Natl Acad Sci U S A. 2014; 112(2):512-7. PMC: 4299213. DOI: 10.1073/pnas.1413291112. View

20.

McDonald J, Celik H, Rois L, Fishberger G, Fowler T, Rees R . Reprogrammable CRISPR/Cas9-based system for inducing site-specific DNA methylation. Biol Open. 2016; 5(6):866-74. PMC: 4920199. DOI: 10.1242/bio.019067. View