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De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation
Abstract
Immune-checkpoint-blockade (ICB)-mediated rejuvenation of exhausted T cells has emerged as a promising approach for treating various cancers and chronic infections. However, T cells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. We report that blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T cell expansion and clonal diversity during PD-1 blockade treatment. Moreover, these exhaustion-associated DNA-methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T cells, and approaches to reverse these programs improved T cell responses and tumor control during ICB. These data establish de novo DNA-methylation programming as a regulator of T cell exhaustion and barrier of ICB-mediated T cell rejuvenation.
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“In antigen-stimulated mouse CD8 + T cells and human chimeric antigen receptor (CAR) T cells, deficiency in DNMT3A or TET2 is associated with normal primary immune responses but enhanced secondary responses with increased memory precursor and central memory T cell differentiation 163-166,183,187 .”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [164]
In the citing paper
“While TET2 deficiency does not result in significant methylation changes at the Eomes locus 163 , DNMT3A deficiency leads to a reduction in Tcf7 promoter methylation, consistent with DNMT3A localization to the Tcf7 promoter in DNMT3A wild-type T cells164.”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [164]
In the citing paper
“These phenotypic changes correlate with increased expression of the master transcription factors TCF1 (encoded by Tcf7) or EOMES in absence of DNMT3A or TET2, respectively[164][165][166]183,187.”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [164]
Citations
Cites
DNA methylation patterns and epigenetic memory
Bird, A. (2002) · Genes & Development · doi:10.1101/gad.947102 · Cited by 7,124
The future of immune checkpoint therapy
Sharma, P., & Allison, J. P. (2015) · Science · doi:10.1126/science.aaa8172 · Cited by 4,878
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062 · cited 11×
“In line with these prior findings, we identified exhaustion-associated de novo programs in the T-bet and Eomes loci among our WGBS data (Figures S4A and S2A).”
InfluentialImmune checkpoint targeting in cancer therapy: toward combination strategies with curative potential
Sharma, P., & Allison, J. P. (2015) · Cell · doi:10.1016/j.cell.2015.03.030 · Cited by 2,345
Linking DNA methylation and histone modification: patterns and paradigms
Cedar, H., & Bergman, Y. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2540 · Cited by 2,267 · cited 2×
“transcription factors and epigenetic modifications are associated with changes in chromatin accessibility, recent evidence supports the notion that DNA methylation is a critical epigenetic mechanism for establishing stable gene-silencing programs (Bintu et al., 2016; Cedar and Bergman, 2009).”
The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation
Wang, R., Dillon, C. P., Shi, L. Z., Milasta, S., Carter, R., Finkelstein, D., McCormick, L. L., Fitzgerald, P., Chi, H., Munger, J., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.09.021 · Cited by 2,140 · cited 2×
“…with the cell’s proliferative potential. c-Myc has been shown to be essential for activationinduced metabolic reprogramming and antigen-driven proliferation of naive CD8 T cells (Wang et al., 2011), and our data revealed that the Myc locus acquires an exhaustion-associated de novo DMR (Figure 1I).”
Self-citationDefining CD8+ T cells that provide the proliferative burst after PD-1 therapy
Im, S. J., Hashimoto, M., Gerner, M. Y., Lee, J., Kissick, H. T., Burger, M. C., Shan, Q., Hale, J. S., Lee, J., Nasti, T. H., et al. (2016) · Nature · doi:10.1038/nature19330 · Cited by 2,070
Chiappinelli, K. B., Strissel, P. L., Desrichard, A., Li, H., Henke, C., Akman, B., Hein, A., Rote, N. S., Cope, L. M., Snyder, A., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.011 · Cited by 2,022
Transcriptional control of effector and memory CD8+ T cell differentiation
Kaech, S. M., & Cui, W. (2012) · Nature Reviews Immunology · doi:10.1038/nri3307 · Cited by 1,628
Wherry, E. J., Blattman, J. N., Murali-Krishna, K., van der Most, R., & Ahmed, R. (2003) · Journal of Virology · doi:10.1128/jvi.77.8.4911-4927.2003 · Cited by 1,610
A census of human transcription factors: function, expression and evolution
Vaquerizas, J. M., Kummerfeld, S. K., Teichmann, S. A., & Luscombe, N. M. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2538 · Cited by 1,573
Roulois, D., Loo Yau, H., Singhania, R., Wang, Y., Danesh, A., Shen, S. Y., Han, H., Liang, G., Jones, P. A., Pugh, T. J., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.056 · Cited by 1,527
Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne, S., Godec, J., Khan, O., Drake, A. M., Chen, Z., Sen, D. R., Kurachi, M., et al. (2016) · Science · doi:10.1126/science.aaf2807 · Cited by 1,348 · cited 3×
“Through efforts to better understand the stable nature of exhaustion-associated transcriptional states, it was recently discovered that the short-lived reinvigoration of T cells during PD-1 blockade therapy was associated with preservation of the chromatin landscape (Pauken et al., 2016).”
InfluentialIMGT(R), the international ImMunoGeneTics information system(R)
Lefranc, M.-P., Giudicelli, V., Ginestoux, C., Jabado-Michaloud, J., Folch, G., Bellahcene, F., Wu, Y., Gemrot, E., Brochet, X., Lane, J., et al. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkn838 · Cited by 1,119
Utzschneider, D. T., Charmoy, M., Chennupati, V., Pousse, L., Ferreira, D. P., Calderon-Copete, S., Danilo, M., Alfei, F., Hofmann, M., Wieland, D., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.07.021 · Cited by 1,085
Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma
Ribas, A., Hamid, O., Daud, A., Hodi, F. S., Wolchok, J. D., Kefford, R., Joshua, A. M., Patnaik, A., Hwu, W.-J., Weber, J. S., et al. (2016) · JAMA · doi:10.1001/jama.2016.4059 · Cited by 1,069
TETonic shift: biological roles of TET proteins in DNA demethylation and transcription
Pastor, W. A., Aravind, L., & Rao, A. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3589 · Cited by 897 · cited 2×
“…cite this article in press as: Ghoneim et al., De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation, Cell (2017), http://dx.doi.org/10.1016/j.cell.2017.06.007 to de-differentiate fate-committed cells (Pastor et al., 2013), specifically exhausted T cells during ICB therapy.”
InfluentialCooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection
Jin, H.-T., Anderson, A. C., Tan, W. G., West, E. E., Ha, S.-J., Araki, K., Freeman, G. J., Kuchroo, V. K., & Ahmed, R. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1009731107 · Cited by 858
Foster, B. A., Gingrich, J. R., Kwon, E. D., Madias, C. A., & Greenberg, N. M. (1997) · PubMed · Cited by 489
Dynamics of epigenetic regulation at the single-cell level
Bintu, L., Yong, J., Antebi, Y. E., McCue, K., Kazuki, Y., Uno, N., Oshimura, M., & Elowitz, M. B. (2016) · Science · doi:10.1126/science.aab2956 · Cited by 441
Li, H., Chiappinelli, K. B., Guzzetta, A. A., Easwaran, H., Yen, R.-W. C., Vatapalli, R., Topper, M. J., Luo, J., Connolly, R. M., Azad, N. S., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.1782 · Cited by 430
Youngblood, B., Oestreich, K. J., Ha, S.-J., Duraiswamy, J., Akondy, R. S., West, E. E., Wei, Z., Lu, P., Austin, J. W., Riley, J. L., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.06.015 · Cited by 419
Self-citationWu, H., Xu, T., Feng, H., Chen, L., Li, B., Yao, B., Qin, Z., Jin, P., & Conneely, K. N. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv715 · Cited by 347
T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?
Speiser, D. E., Utzschneider, D. T., Oberle, S. G., Münz, C., Romero, P., & Zehn, D. (2014) · Nature Reviews Immunology · doi:10.1038/nri3740 · Cited by 302
Angelosanto, J., Blackburn, S. D., Crawford, A., & Wherry, E. J. (2012) · Journal of Virology · doi:10.1128/jvi.00889-12 · Cited by 292
T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion
Utzschneider, D. T., Legat, A., Marraco, S. A. F., Carrié, L., Luescher, I. F., Speiser, D. E., & Zehn, D. (2013) · Nature Immunology · doi:10.1038/ni.2606 · Cited by 289
Russ, B. E., Olshanksy, M., Smallwood, H. S., Li, J., Denton, A. E., Prier, J. E., Stock, A. T., McQuilten, H. A., Cullen, J. G., Nguyen, M. L. T., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.11.001 · Cited by 223
Self-citationGlobal DNA Methylation Remodeling Accompanies CD8 T Cell Effector Function
Scharer, C. D., Barwick, B. G., Youngblood, B., Ahmed, R., & Boss, J. M. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301395 · Cited by 214
Self-citationHa, S., Mueller, S. N., Wherry, E. J., Barber, D. L., Aubert, R. D., Sharpe, A. H., Freeman, G. J., & Ahmed, R. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20071949 · Cited by 212
Paired analysis of TCRα and TCRβ chains at the single-cell level in mice
Dash, P., McClaren, J. L., Oguin, T. H., Rothwell, W. T., Todd, B., Morris, M. Y., Becksfort, J. B., Reynolds, C., Brown, S. A., Doherty, P. C., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci44752 · Cited by 199
Self-citationWang, L., Amoozgar, Z., Huang, J., Saleh, M. H., Xing, D., Orsulic, S., & Goldberg, M. S. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0073 · Cited by 173
DNA Methylation Analysis by MethyLight Technology
Trinh, B. N., Long, T. I., & Laird, P. W. (2001) · Methods · doi:10.1006/meth.2001.1268 · Cited by 140
Tumor Vaccines Expressing Flt3 Ligand Synergize with CTLA-4 Blockade to Reject Preimplanted Tumors
Curran, M. A., & Allison, J. P. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3289 · Cited by 132
Crompton, J. G., Narayanan, M., Cuddapah, S., Roychoudhuri, R., Ji, Y., Yang, W., Patel, S. J., Sukumar, M., Palmer, D. C., Peng, W., et al. (2015) · Cellular and Molecular Immunology · doi:10.1038/cmi.2015.32 · Cited by 123
Matloubian, M., Somasundaram, T., Kolhekar, S. R., Selvakumar, R., & Ahmed, R. (1990) · The Journal of Experimental Medicine · doi:10.1084/jem.172.4.1043 · Cited by 123
Yu, P., Steel, J. C., Zhang, M., Morris, J. C., Waitz, R., Fassò, M., Allison, J. P., & Waldmann, T. A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1203479109 · Cited by 116
Chiappinelli, K. B., Strissel, P. L., Desrichard, A., Li, H., Henke, C., Akman, B., Hein, A., Rote, N. S., Cope, L., Snyder, A., et al. (2016) · Cell · doi:10.1016/j.cell.2015.10.020 · Cited by 80
Cell-Intrinsic Barriers of T Cell-Based Immunotherapy
Ghoneim, H. E., Zamora, A. E., Thomas, P. G., & Youngblood, B. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.10.002 · Cited by 72
Self-citationThomas, P. G., Handel, A., Doherty, P. C., & Gruta, N. L. L. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1222149110 · Cited by 53
Self-citationSingle-Cell Analysis of T-Cell Receptor αβ Repertoire
Dash, P., Wang, G. C., & Thomas, P. G. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-2963-4_15 · Cited by 31
Self-citation
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Fundamental Mechanisms of Immune Checkpoint Blockade Therapy
Wei, S. C., Duffy, C. R., & Allison, J. P. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0367 · Cited by 3,088
TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion
Khan, O., Giles, J. R., McDonald, S., Manne, S., Ngiow, S. F., Patel, K. P., Werner, M. T., Huang, A. C., Alexander, K. A., Wu, J. E., et al. (2019) · Nature · doi:10.1038/s41586-019-1325-x · Cited by 1,646
Clonal replacement of tumor-specific T cells following PD-1 blockade
Yost, K. E., Satpathy, A. T., Wells, D. K., Qi, Y., Wang, C., Kageyama, R., McNamara, K. L., Granja, J. M., Sarin, K. Y., Brown, R. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0522-3 · Cited by 1,534
Blank, C. U., Haining, W. N., Held, W., Hogan, P. G., Kallies, A., Lugli, E., Lynn, R. C., Philip, M., Rao, A., Restifo, N. P., et al. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0221-9 · Cited by 1,603
Self-citationClinical implications of T cell exhaustion for cancer immunotherapy
Chow, A., Perica, K., Klebanoff, C. A., & Wolchok, J. D. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00689-z · Cited by 1,044
Metadata
- Authors
- Ghoneim, H. E., Fan, Y., Moustaki, A., Abdelsamed, H. A., Dash, P., Dogra, P., Carter, R., Awad, W., Neale, G., Thomas, P. G., & Youngblood, B.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 170
- Issue
- 1
- Pages
- 142-157.e19
- ISSN
- 0092-8674
- Cited by
- 781
- References
- 40
- Language
- en
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 393 d)
- Funders
- National Institutes of Health (1R01AI114442)
- ALSAC
- SJCRH Garwood Postdoctoral Fellowship
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