Abstract
The past decade has seen the emergence of immunotherapy as a prime approach to cancer treatment, revolutionizing the management of many types of cancer. Despite the promise of immunotherapy, most patients do not have a response or become resistant to treatment. Thus, identifying combinations that potentiate current immunotherapeutic approaches will be crucial. The combination of immune-checkpoint inhibition with epigenetic therapy is one such strategy that is being tested in clinical trials, encompassing a variety of cancer types. Studies have revealed key roles of epigenetic processes in regulating immune cell function and mediating antitumour immunity. These interactions make combined epigenetic therapy and immunotherapy an attractive approach to circumvent the limitations of immunotherapy alone. In this Review, we highlight the basic dynamic mechanisms underlying the synergy between immunotherapy and epigenetic therapies and detail current efforts to translate this knowledge into clinical benefit for patients.
Key points
-
The past decade has witnessed the emergence of immune-checkpoint inhibition as the potential fourth pillar of anticancer therapy; however, combination therapeutic paradigms are needed to maximize benefits and overcome resistance to immune-checkpoint inhibition.
-
Epigenetic therapy has the ability to modulate the tumour microenvironment, for example, by inducing both the accumulation and infiltration of CD8+ lymphocytes through interferon-dependent, chemokine-mediated chemotaxis.
-
Epigenetic therapy can also prevent the emergence and/or acquisition of an epigenetic programme of T cell exhaustion and can facilitate the formation of CD8+ effector and/or memory T cells.
-
Histone deacetylase inhibitors can affect the tumour myeloid compartment by causing myeloid-derived suppressor cell depletion, differentiation and functional antagonism.
-
Epigenetic modulators can enhance tumour cell recognition and potentiate type I interferon responses through MYC and MYC-related target downregulation.
-
The combination of epigenetic drugs and immunotherapy is emerging as a crucial therapeutic paradigm across a variety of malignancies.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).
Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).
Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010).
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).
Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).
Motzer, R. J. et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J. Clin. Oncol. 33, 1430–1437 (2015).
Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).
Ansell, S. M. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372, 311–319 (2015).
Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).
Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).
Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).
Forde, P. M., Chaft, J. E. & Pardoll, D. M. Neoadjuvant PD-1 blockade in resectable lung cancer. N. Engl. J. Med. 379, e14 (2018).
Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).
Decker, W. K. et al. Cancer immunotherapy: historical perspective of a clinical revolution and emerging preclinical animal models. Front. Immunol. 8, 829 (2017).
Tahmasebi, S., Elahi, R. & Esmaeilzadeh, A. Solid tumors challenges and new insights of CAR T cell engineering. Stem Cell Rev. 15, 619–636 (2019).
Brown, M. P., Ebert, L. M. & Gargett, T. Clinical chimeric antigen receptor-T cell therapy: a new and promising treatment modality for glioblastoma. Clin. Transl Immunology 8, e1050 (2019).
Berzofsky, J. A. et al. Cancer vaccine strategies: translation from mice to human clinical trials. Cancer Immunol. Immunother. 67, 1863–1869 (2018).
Banday, A. H., Jeelani, S. & Hruby, V. J. Cancer vaccine adjuvants–recent clinical progress and future perspectives. Immunopharmacol. Immunotoxicol. 37, 1–11 (2015).
Mougel, A., Terme, M. & Tanchot, C. Therapeutic cancer vaccine and combinations with antiangiogenic therapies and immune checkpoint blockade. Front. Immunol. 10, 467 (2019).
Fang, F., Xiao, W. & Tian, Z. NK cell-based immunotherapy for cancer. Semin. Immunol. 31, 37–54 (2017).
Muntasell, A. et al. Targeting NK-cell checkpoints for cancer immunotherapy. Curr. Opin. Immunol. 45, 73–81 (2017).
Becker, P. S. et al. Selection and expansion of natural killer cells for NK cell-based immunotherapy. Cancer Immunol. Immunother. 65, 477–484 (2016).
Heong, V., Ngoi, N. & Tan, D. S. Update on immune checkpoint inhibitors in gynecological cancers. J. Gynecol. Oncol. 28, e20 (2017).
Strasner, A. & Karin, M. Immune infiltration and prostate cancer. Front. Oncol. 5, 128 (2015).
Auvray, M. et al. Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma. Eur. J. Cancer 108, 33–40 (2019).
Skoulidis, F. et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8, 822–835 (2018).
Pham, T. et al. An update on immunotherapy for solid tumors: a review. Ann. Surg. Oncol. 25, 3404–3412 (2018).
Torphy, R. J., Zhu, Y. & Schulick, R. D. Immunotherapy for pancreatic cancer: barriers and breakthroughs. Ann. Gastroenterol. Surg. 2, 274–281 (2018).
Royal, R. E. et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).
Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).
Schmid, P. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).
Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).
Hodi, F. S. et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 19, 1480–1492 (2018).
Gandhi, L. et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med. 378, 2078–2092 (2018).
Paz-Ares, L. et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N. Engl. J. Med. 379, 2040–2051 (2018).
Antonia, S. J. et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 377, 1919–1929 (2017).
Alomari, A. K. et al. Possible interaction of anti-PD-1 therapy with the effects of radiosurgery on brain metastases. Cancer Immunol. Res. 4, 481–487 (2016).
Haymaker, C. L. et al. Metastatic melanoma patient had a complete response with clonal expansion after whole brain radiation and PD-1 blockade. Cancer Immunol. Res. 5, 100–105 (2017).
Nagasaka, M. et al. PD1/PD-L1 inhibition as a potential radiosensitizer in head and neck squamous cell carcinoma: a case report. J. Immunother. Cancer 4, 83 (2016).
Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).
Okazaki, T. & Honjo, T. PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 19, 813–824 (2007).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).
Rabinovich, G. A., Gabrilovich, D. & Sotomayor, E. M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 25, 267–296 (2007).
Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
Marincola, F. M., Jaffee, E. M., Hicklin, D. J. & Ferrone, S. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv. Immunol. 74, 181–273 (2000).
Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).
Stamper, C. C. et al. Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature 410, 608–611 (2001).
Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).
Yamazaki, T. et al. Expression of programmed death 1 ligands by murine T cells and APC. J. Immunol. 169, 5538–5545 (2002).
Kuang, D. M. et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327–1337 (2009).
Pander, J. et al. Activation of tumor-promoting type 2 macrophages by EGFR-targeting antibody cetuximab. Clin. Cancer Res. 17, 5668–5673 (2011).
Zahavi, D. J. & Weiner, L. M. Targeting multiple receptors to increase checkpoint blockade efficacy. Int. J. Mol. Sci. 20, E158 (2019).
Pages, F. et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J. Clin. Oncol. 27, 5944–5951 (2009).
Galon, J. et al. Towards the introduction of the 'immunoscore' in the classification of malignant tumours. J. Pathol. 232, 199–209 (2014).
Lanitis, E., Dangaj, D., Irving, M. & Coukos, G. Mechanisms regulating T-cell infiltration and activity in solid tumors. Ann. Oncol. 28, xii18–xii32 (2017).
Peranzoni, E. et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. Proc. Natl Acad. Sci. USA 115, E4041–E4050 (2018).
Shin, J. I. & Ha, S. J. Regulatory T cells-an important target for cancer immunotherapy. Nat. Rev. Clin. Oncol. 11, 307 (2014).
Woo, E. Y. et al. Regulatory CD4+CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 61, 4766–4772 (2001).
Togashi, Y., Shitara, K. & Nishikawa, H. Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat. Rev. Clin. Oncol. 16, 356–371 (2019).
de Charette, M., Marabelle, A. & Houot, R. Turning tumour cells into antigen presenting cells: the next step to improve cancer immunotherapy? Eur. J. Cancer 68, 134–147 (2016).
Beatty, G. L. & Gladney, W. L. Immune escape mechanisms as a guide for cancer immunotherapy. Clin. Cancer Res. 21, 687–692 (2015).
Dustin, M. L. The immunological synapse. Cancer Immunol. Res. 2, 1023–1033 (2014).
Tamada, K. [Development of novel immunotherapy targeting cancer immune evasion]. Gan Kagaku Ryoho 41, 1062–1065 (2014).
Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).
Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).
Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to pd-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017).
Spranger, S. et al. Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma. Proc. Natl Acad. Sci. USA 113, E7759–E7768 (2016).
Turajlic, S. et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 18, 1009–1021 (2017).
Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683–692 (2007).
Baylin, S. B. The cancer epigenome: its origins, contributions to tumorigenesis, and translational implications. Proc. Am. Thorac. Soc. 9, 64–65 (2012).
Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome — biological and translational implications. Nat. Rev. Cancer 11, 726–734 (2011).
Shen, H. & Laird, P. W. Interplay between the cancer genome and epigenome. Cell 153, 38–55 (2013).
Baylin, S. B. & Jones, P. A. Epigenetic determinants of cancer. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a019505 (2016).
Esteller, M. Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum. Mol. Genet. 16, R50–R59 (2007).
Portela, A. & Esteller, M. Epigenetic modifications and human disease. Nat. Biotechnol. 28, 1057–1068 (2010).
Esteller, M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat. Rev. Genet. 8, 286–298 (2007).
Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).
Struhl, K. & Segal, E. Determinants of nucleosome positioning. Nat. Struct. Mol. Biol. 20, 267–273 (2013).
Allis, C. D., Jenuwein, T., Reinberg, D. & Caparros, M. in Epigenetics 2nd edn (Cold Spring Harbor Laboratory Research Press, 2015).
Hyun, K., Jeon, J., Park, K. & Kim, J. Writing, erasing and reading histone lysine methylations. Exp. Mol. Med. 49, e324 (2017).
Allis, C. D. & Jenuwein, T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 17, 487–500 (2016).
Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).
Zhou, V. W., Goren, A. & Bernstein, B. E. Charting histone modifications and the functional organization of mammalian genomes. Nat. Rev. Genet. 12, 7–18 (2011).
Bonasio, R., Tu, S. & Reinberg, D. Molecular signals of epigenetic states. Science 330, 612–616 (2010).
Pfister, S. X. & Ashworth, A. Marked for death: targeting epigenetic changes in cancer. Nat. Rev. Drug Discov. 16, 241–263 (2017).
Skulte, K. A., Phan, L., Clark, S. J. & Taberlay, P. C. Chromatin remodeler mutations in human cancers: epigenetic implications. Epigenomics 6, 397–414 (2014).
Suva, M. L., Riggi, N. & Bernstein, B. E. Epigenetic reprogramming in cancer. Science 339, 1567–1570 (2013).
Easwaran, H., Tsai, H. C. & Baylin, S. B. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol. Cell 54, 716–727 (2014).
Kulis, M. & Esteller, M. DNA methylation and cancer. Adv. Genet. 70, 27–56 (2010).
Herman, J. G. et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl Acad. Sci. USA 95, 6870–6875 (1998).
Wong, D. J., Barrett, M. T., Stoger, R., Emond, M. J. & Reid, B. J. p16INK4a promoter is hypermethylated at a high frequency in esophageal adenocarcinomas. Cancer Res. 57, 2619–2622 (1997).
Klump, B., Hsieh, C. J., Holzmann, K., Gregor, M. & Porschen, R. Hypermethylation of the CDKN2/p16 promoter during neoplastic progression in Barrett's esophagus. Gastroenterology 115, 1381–1386 (1998).
Jones, P. A. & Laird, P. W. Cancer epigenetics comes of age. Nat. Genet. 21, 163–167 (1999).
Kron, K. J., Bailey, S. D. & Lupien, M. Enhancer alterations in cancer: a source for a cell identity crisis. Genome Med. 6, 77 (2014).
Aran, D. & Hellman, A. DNA methylation of transcriptional enhancers and cancer predisposition. Cell 154, 11–13 (2013).
Hnisz, D., Day, D. S. & Young, R. A. Insulated neighborhoods: structural and functional units of mammalian gene control. Cell 167, 1188–1200 (2016).
Aran, D. & Hellman, A. Unmasking risk loci: DNA methylation illuminates the biology of cancer predisposition: analyzing DNA methylation of transcriptional enhancers reveals missed regulatory links between cancer risk loci and genes. Bioessays 36, 184–190 (2014).
Loven, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).
Chi, P., Allis, C. D. & Wang, G. G. Covalent histone modifications–miswritten, misinterpreted and mis-erased in human cancers. Nat. Rev. Cancer 10, 457–469 (2010).
Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).
Cameron, E. E., Bachman, K. E., Myohanen, S., Herman, J. G. & Baylin, S. B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat. Genet. 21, 103–107 (1999).
Verdone, L., Caserta, M. & Di Mauro, E. Role of histone acetylation in the control of gene expression. Biochem. Cell Biol. 83, 344–353 (2005).
Gallinari, P., Di Marco, S., Jones, P., Pallaoro, M. & Steinkuhler, C. HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics. Cell Res. 17, 195–211 (2007).
El-Osta, A. & Wolffe, A. P. DNA methylation and histone deacetylation in the control of gene expression: basic biochemistry to human development and disease. Gene Expr. 9, 63–75 (2000).
Irvine, R. A., Lin, I. G. & Hsieh, C. L. DNA methylation has a local effect on transcription and histone acetylation. Mol. Cell Biol. 22, 6689–6696 (2002).
Struhl, K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 12, 599–606 (1998).
Zahnow, C. A. et al. Inhibitors of dna methylation, histone deacetylation, and histone demethylation: a perfect combination for cancer therapy. Adv. Cancer Res. 130, 55–111 (2016).
Jones, P. A., Issa, J. P. & Baylin, S. Targeting the cancer epigenome for therapy. Nat. Rev. Genet. 17, 630–641 (2016).
Tripathi, S. K. & Lahesmaa, R. Transcriptional and epigenetic regulation of T-helper lineage specification. Immunol. Rev. 261, 62–83 (2014).
Shih, H. Y. et al. Transcriptional and epigenetic networks of helper T and innate lymphoid cells. Immunol. Rev. 261, 23–49 (2014).
Wilson, C. B., Makar, K. W. & Perez-Melgosa, M. Epigenetic regulation of T cell fate and function. J. Infect. Dis. 185, S37–S45 (2002).
Hu, G. et al. Transformation of accessible chromatin and 3D nucleome underlies lineage commitment of early T cells. Immunity 48, 227–242.e8 (2018).
Johnson, J. L. et al. Lineage-determining transcription factor TCF-1 initiates the epigenetic identity of t cells. Immunity 48, 243–257.e10 (2018).
Zheng, H. et al. HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin. Cancer Res. 22, 4119–4132 (2016).
Youngblood, B. et al. Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature 552, 404–409 (2017).
Ghoneim, H. E. et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170, 142–157.e19 (2017).
Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).
Chang, J. T., Wherry, E. J. & Goldrath, A. W. Molecular regulation of effector and memory T cell differentiation. Nat. Immunol. 15, 1104–1115 (2014).
Carty, S. A. et al. The loss of TET2 promotes CD8+ T cell memory differentiation. J. Immunol. 200, 82–91 (2018).
Scharer, C. D., Bally, A. P., Gandham, B. & Boss, J. M. Cutting edge: chromatin accessibility programs CD8 T cell memory. J. Immunol. 198, 2238–2243 (2017).
Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492–499 (2011).
Hashimoto, M. et al. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu. Rev. Med. 69, 301–318 (2018).
Youngblood, B. et al. Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8+ T cells. Immunity 35, 400–412 (2011).
Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).
Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).
Alvarez-Errico, D., Vento-Tormo, R., Sieweke, M. & Ballestar, E. Epigenetic control of myeloid cell differentiation, identity and function. Nat. Rev. Immunol. 15, 7–17 (2015).
Ivashkiv, L. B. & Park, S. H. Epigenetic regulation of myeloid cells. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.MCHD-0010-2015 (2016).
Srivastava, M. K., Sinha, P., Clements, V. K., Rodriguez, P. & Ostrand-Rosenberg, S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 70, 68–77 (2010).
Zhang, H. et al. Myeloid-derived suppressor cells inhibit T cell proliferation in human extranodal NK/T cell lymphoma: a novel prognostic indicator. Cancer Immunol. Immunother. 64, 1587–1599 (2015).
Nagaraj, S., Schrum, A. G., Cho, H. I., Celis, E. & Gabrilovich, D. I. Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J. Immunol. 184, 3106–3116 (2010).
Rodriguez, R. M., Suarez-Alvarez, B. & Lopez-Larrea, C. Therapeutic epigenetic reprogramming of trained immunity in myeloid cells. Trends Immunol. 40, 66–80 (2019).
de Groot, A. E. & Pienta, K. J. Epigenetic control of macrophage polarization: implications for targeting tumor-associated macrophages. Oncotarget 9, 20908–20927 (2018).
Travers, M. et al. DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of murine ovarian cancer. Cancer Res. 79, 3445–3454 (2019).
Tsai, H. C. & Baylin, S. B. Cancer epigenetics: linking basic biology to clinical medicine. Cell Res. 21, 502–517 (2011).
Tsai, H. C. et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21, 430–446 (2012).
Baylin, S. B. & Ohm, J. E. Epigenetic gene silencing in cancer — a mechanism for early oncogenic pathway addiction? Nat. Rev. Cancer 6, 107–116 (2006).
Issa, J. J. et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 16, 1099–1110 (2015).
Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).
Wrangle, J. et al. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget 4, 2067–2079 (2013).
Li, H. et al. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 5, 587–598 (2014).
Topper, M. J. et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer. Cell 171, 1284–1300.e21 (2017).
Heninger, E., Krueger, T. E. & Lang, J. M. Augmenting antitumor immune responses with epigenetic modifying agents. Front. Immunol. 6, 29 (2015).
Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsrna including endogenous retroviruses. Cell 162, 974–986 (2015).
Roulois, D. et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 961–973 (2015).
Natsume, A. et al. The DNA demethylating agent 5-aza-2'-deoxycytidine activates NY-ESO-1 antigenicity in orthotopic human glioma. Int. J. Cancer 122, 2542–2553 (2008).
Moreno-Bost, A. et al. Epigenetic modulation of MAGE-A3 antigen expression in multiple myeloma following treatment with the demethylation agent 5-azacitidine and the histone deacetlyase inhibitor MGCD0103. Cytotherapy 13, 618–628 (2011).
Almstedt, M. et al. The DNA demethylating agent 5-aza-2'-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells. Leuk. Res. 34, 899–905 (2010).
Goodyear, O. et al. Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood 116, 1908–1918 (2010).
James, S. R., Link, P. A. & Karpf, A. R. Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b. Oncogene 25, 6975–6985 (2006).
Weber, J. et al. Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2'-deoxycytidine. Cancer Res. 54, 1766–1771 (1994).
De Smet, C. et al. The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc. Natl Acad. Sci. USA 93, 7149–7153 (1996).
Li, J. et al. Expression of BAGE, GAGE, and MAGE genes in human gastric carcinoma. Clin. Cancer Res. 2, 1619–1625 (1996).
Sigalotti, L. et al. Promoter methylation controls the expression of MAGE2, 3 and 4 genes in human cutaneous melanoma. J. Immunother. 25, 16–26 (2002).
De Smet, C., Lurquin, C., Lethe, B., Martelange, V. & Boon, T. DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter. Mol. Cell Biol. 19, 7327–7335 (1999).
Maatouk, D. M. et al. DNA methylation is a primary mechanism for silencing postmigratory primordial germ cell genes in both germ cell and somatic cell lineages. Development 133, 3411–3418 (2006).
Fratta, E. et al. The biology of cancer testis antigens: putative function, regulation and therapeutic potential. Mol. Oncol. 5, 164–182 (2011).
Ritter, C. et al. Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma. Sci. Rep. 7, 2290 (2017).
Ramsuran, V. et al. Epigenetic regulation of differential HLA-A allelic expression levels. Hum. Mol. Genet. 24, 4268–4275 (2015).
Coral, S. et al. Prolonged upregulation of the expression of HLA class I antigens and costimulatory molecules on melanoma cells treated with 5-aza-2'-deoxycytidine (5-AZA-CdR). J. Immunother. 22, 16–24 (1999).
Nie, Y. et al. DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas. Carcinogenesis 22, 1615–1623 (2001).
Karpf, A. R. et al. Inhibition of DNA methyltransferase stimulates the expression of signal transducer and activator of transcription 1, 2, and 3 genes in colon tumor cells. Proc. Natl Acad. Sci. USA 96, 14007–14012 (1999).
Griffiths, D. J. Endogenous retroviruses in the human genome sequence. Genome Biol. 2, REVIEWS1017 (2001).
Lavie, L., Kitova, M., Maldener, E., Meese, E. & Mayer, J. CpG methylation directly regulates transcriptional activity of the human endogenous retrovirus family HERV-K(HML-2). J. Virol. 79, 876–883 (2005).
Szpakowski, S. et al. Loss of epigenetic silencing in tumors preferentially affects primate-specific retroelements. Gene 448, 151–167 (2009).
Brady, T. et al. Integration target site selection by a resurrected human endogenous retrovirus. Genes Dev. 23, 633–642 (2009).
Jones, P. A., Ohtani, H., Chakravarthy, A. & De Carvalho, D. D. Epigenetic therapy in immune-oncology. Nat. Rev. Cancer 19, 151–161 (2019).
Juergens, R. A. et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 1, 598–607 (2011).
Wang, L. et al. Decitabine enhances lymphocyte migration and function and synergizes with CTLA-4 blockade in a murine ovarian cancer model. Cancer Immunol. Res. 3, 1030–1041 (2015).
Luo, N. et al. DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer. Nat. Commun. 9, 248 (2018).
Yu, G. et al. Low-dose decitabine enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by re-modulating the tumor microenvironment. Cell Mol. Immunol. 16, 401–409 (2018).
Woods, D. M. et al. HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol. Res. 3, 1375–1385 (2015).
Llopiz, D. et al. Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor belinostat in a murine hepatocellular carcinoma model. Cancer Immunol. Immunother. 68, 379–393 (2018).
Kim, K. et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc. Natl Acad. Sci. USA 111, 11774–11779 (2014).
Orillion, A. et al. Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin. Cancer Res. 23, 5187–5201 (2017).
Stone, M. L. et al. Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden. Proc. Natl Acad. Sci. USA 114, E10981–E10990 (2017).
Kawai, T. et al. Selective diapedesis of Th1 cells induced by endothelial cell RANTES. J. Immunol. 163, 3269–3278 (1999).
Schall, T. J., Bacon, K., Toy, K. J. & Goeddel, D. V. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature 347, 669–671 (1990).
Lederman, M. M., Penn-Nicholson, A., Cho, M. & Mosier, D. Biology of CCR5 and its role in HIV infection and treatment. JAMA 296, 815–826 (2006).
Stanford, M. M. & Issekutz, T. B. The relative activity of CXCR3 and CCR5 ligands in T lymphocyte migration: concordant and disparate activities in vitro and in vivo. J. Leukoc. Biol. 74, 791–799 (2003).
Moran, C. J. et al. RANTES expression is a predictor of survival in stage I lung adenocarcinoma. Clin. Cancer Res. 8, 3803–3812 (2002).
Kortlever, R. M. et al. Myc cooperates with Ras by programming inflammation and immune suppression. Cell 171, 1301–1315.e14 (2017).
Casey, S. C. et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352, 227–231 (2016).
Folkes, A. S. et al. Targeting CD47 as a cancer therapeutic strategy: the cutaneous T-cell lymphoma experience. Curr. Opin. Oncol. 30, 332–337 (2018).
Daver, N. et al. Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: a nonrandomized, open-label, phase II study. Cancer Discov. 9, 370–383 (2019).
Levy, B. P. et al. Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer. Eur. J. Cancer 108, 120–128 (2019).
Savona, M. R. et al. Extended dosing with CC-486 (oral azacitidine) in patients with myeloid malignancies. Am. J. Hematol. 93, 1199–1206 (2018).
Genta, S., Pirosa, M. C. & Stathis, A. BET and EZH2 inhibitors: novel approaches for targeting cancer. Curr. Oncol. Rep. 21, 13 (2019).
Kim, K. H. & Roberts, C. W. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).
Margueron, R. & Reinberg, D. The polycomb complex PRC2 and its mark in life. Nature 469, 343–349 (2011).
Yamagishi, M. & Uchimaru, K. Targeting EZH2 in cancer therapy. Curr. Opin. Oncol. 29, 375–381 (2017).
Schlesinger, Y. et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat. Genet. 39, 232–236 (2007).
Widschwendter, M. et al. Epigenetic stem cell signature in cancer. Nat. Genet. 39, 157–158 (2007).
Easwaran, H. et al. A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Res. 22, 837–849 (2012).
Ohm, J. E. & Baylin, S. B. Stem cell chromatin patterns: an instructive mechanism for DNA hypermethylation? Cell Cycle 6, 1040–1043 (2007).
Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).
Goswami, S. et al. Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J. Clin. Invest. 128, 3813–3818 (2018).
Zingg, D. et al. The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy. Cell Rep. 20, 854–867 (2017).
Hosseini, A. & Minucci, S. A comprehensive review of lysine-specific demethylase 1 and its roles in cancer. Epigenomics 9, 1123–1142 (2017).
Wang, J. et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat. Genet. 41, 125–129 (2009).
Morera, L., Lubbert, M. & Jung, M. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin. Epigenetics 8, 57 (2016).
Han, H., Yang, X., Pandiyan, K. & Liang, G. Synergistic re-activation of epigenetically silenced genes by combinatorial inhibition of DNMTs and LSD1 in cancer cells. PLOS ONE 8, e75136 (2013).
Yang, G. J., Lei, P. M., Wong, S. Y., Ma, D. L. & Leung, C. H. Pharmacological inhibition of LSD1 for cancer treatment. Molecules 23, E3194 (2018).
Sheng, W. et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell 174, 549–563.e19 (2018).
Qin, Y. et al. Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade. Oncogene 38, 390–405 (2019).
Esteve, P. O. et al. Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev. 20, 3089–3103 (2006).
Huang, T. et al. G9A promotes tumor cell growth and invasion by silencing CASP1 in non-small-cell lung cancer cells. Cell Death Dis. 8, e2726 (2017).
Casciello, F., Windloch, K., Gannon, F. & Lee, J. S. Functional role of G9a histone methyltransferase in cancer. Front. Immunol. 6, 487 (2015).
Hu, L. et al. G9A promotes gastric cancer metastasis by upregulating ITGB3 in a SET domain-independent manner. Cell Death Dis. 9, 278 (2018).
Ma, D. K., Chiang, C. H., Ponnusamy, K., Ming, G. L. & Song, H. G9a and Jhdm2a regulate embryonic stem cell fusion-induced reprogramming of adult neural stem cells. Stem Cells 26, 2131–2141 (2008).
Liu, M. et al. Dual inhibition of dna and histone methyltransferases increases viral mimicry in ovarian cancer cells. Cancer Res. 78, 5754–5766 (2018).
Di Giacomo, M., Comazzetto, S., Sampath, S. C., Sampath, S. C. & O'Carroll, D. G9a co-suppresses LINE1 elements in spermatogonia. Epigenetics Chromatin 7, 24 (2014).
Zeng, L. & Zhou, M. M. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 513, 124–128 (2002).
Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010).
Perez-Salvia, M. & Esteller, M. Bromodomain inhibitors and cancer therapy: from structures to applications. Epigenetics 12, 323–339 (2017).
Xu, Y. & Vakoc, C. R. Targeting cancer cells with bet bromodomain inhibitors. Cold Spring Harb. Perspect. Med. 7, a026674 (2017).
Tang, Y. et al. Epigenetic targeting of hedgehog pathway transcriptional output through bet bromodomain inhibition. Nat. Med. 20, 732–740 (2014).
Adeegbe, D. O. et al. BET bromodomain inhibition cooperates with PD-1 blockade to facilitate antitumor response in KRAS-mutant non-small cell lung cancer. Cancer Immunol. Res. 6, 1234–1245 (2018).
Lu, D. et al. Treatment with demethylating agent, 5-aza-2'-deoxycytidine enhances therapeutic HPV DNA vaccine potency. Vaccine 27, 4363–4369 (2009).
Vo, D. D. et al. Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824. Cancer Res. 69, 8693–8699 (2009).
Gonzalez, H., Hagerling, C. & Werb, Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev. 32, 1267–1284 (2018).
Teng, M. W., Ngiow, S. F., Ribas, A. & Smyth, M. J. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res. 75, 2139–2145 (2015).
Galon, J. & Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov. 18, 197–218 (2019).
Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).
Taube, J. M. et al. Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med. 4, 127ra37 (2012).
Ribas, A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 5, 915–919 (2015).
Zou, W. & Chen, L. Inhibitory B7-family molecules in the tumour microenvironment. Nat. Rev. Immunol. 8, 467–477 (2008).
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Pages, F. et al. International validation of the consensus immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 391, 2128–2139 (2018).
Huang, R. R. et al. CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans. Clin. Cancer Res. 17, 4101–4109 (2011).
Bald, T. et al. Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation. Cancer Discov. 4, 674–687 (2014).
Kershaw, M. H., Westwood, J. A. & Darcy, P. K. Gene-engineered T cells for cancer therapy. Nat. Rev. Cancer 13, 525–541 (2013).
Parsa, A. T. et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat. Med. 13, 84–88 (2007).
Marzec, M. et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc. Natl Acad. Sci. USA 105, 20852–20857 (2008).
Spranger, S. & Gajewski, T. F. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer 18, 139–147 (2018).
Schietinger, A. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389–401 (2016).
Spranger, S. Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. Int. Immunol. 28, 383–391 (2016).
Leone, R. D. & Emens, L. A. Targeting adenosine for cancer immunotherapy. J. Immunother. Cancer 6, 57 (2018).
Yentz, S. & Smith, D. Indoleamine 2,3-dioxygenase (IDO) inhibition as a strategy to augment cancer immunotherapy. BioDrugs 32, 311–317 (2018).
Makkouk, A. & Weiner, G. J. Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge. Cancer Res. 75, 5–10 (2015).
Scharer, C. D., Barwick, B. G., Youngblood, B. A., Ahmed, R. & Boss, J. M. Global DNA methylation remodeling accompanies CD8 T cell effector function. J. Immunol. 191, 3419–3429 (2013).
Haring, J. S., Badovinac, V. P. & Harty, J. T. Inflaming the CD8+ T cell response. Immunity 25, 19–29 (2006).
Pozzi, L. A., Maciaszek, J. W. & Rock, K. L. Both dendritic cells and macrophages can stimulate naive CD8 T cells in vivo to proliferate, develop effector function, and differentiate into memory cells. J. Immunol. 175, 2071–2081 (2005).
Pennock, N. D. et al. T cell responses: naive to memory and everything in between. Adv. Physiol. Educ. 37, 273–283 (2013).
Appleman, L. J. & Boussiotis, V. A. T cell anergy and costimulation. Immunol. Rev. 192, 161–180 (2003).
Allison, J. P. CD28-B7 interactions in T-cell activation. Curr. Opin. Immunol. 6, 414–419 (1994).
Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242 (2013).
Umlauf, S. W., Beverly, B., Lantz, O. & Schwartz, R. H. Regulation of interleukin 2 gene expression by CD28 costimulation in mouse T-cell clones: both nuclear and cytoplasmic RNAs are regulated with complex kinetics. Mol. Cell Biol. 15, 3197–3205 (1995).
Curtsinger, J. M. & Mescher, M. F. Inflammatory cytokines as a third signal for T cell activation. Curr. Opin. Immunol. 22, 333–340 (2010).
Ramos, H. J. et al. Reciprocal responsiveness to interleukin-12 and interferon-α specifies human CD8+ effector versus central memory T-cell fates. Blood 113, 5516–5525 (2009).
Xiao, S. et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-β-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J. Immunol. 181, 2277–2284 (2008).
Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).
Kaech, S. M. & Wherry, E. J. Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity 27, 393–405 (2007).
Hokeness, K. L. et al. CXCR3-dependent recruitment of antigen-specific T lymphocytes to the liver during murine cytomegalovirus infection. J. Virol. 81, 1241–1250 (2007).
Ahn, E. et al. Role of PD-1 during effector CD8 T cell differentiation. Proc. Natl Acad. Sci. USA 115, 4749–4754 (2018).
Okazaki, T., Maeda, A., Nishimura, H., Kurosaki, T. & Honjo, T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc. Natl Acad. Sci. USA 98, 13866–13871 (2001).
Brinkman, C. C., Peske, J. D. & Engelhard, V. H. Peripheral tissue homing receptor control of naive, effector, and memory CD8 T cell localization in lymphoid and non-lymphoid tissues. Front. Immunol. 4, 241 (2013).
Angelosanto, J. M., Blackburn, S. D., Crawford, A. & Wherry, E. J. Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. J. Virol. 86, 8161–8170 (2012).
Qin, S. et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J. Clin. Invest. 101, 746–754 (1998).
Ribas, A. et al. PD-1 blockade expands intratumoral memory T cells. Cancer Immunol. Res. 4, 194–203 (2016).
Gerlach, C. et al. The chemokine receptor cx3cr1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity 45, 1270–1284 (2016).
Acknowledgements
The work of the authors is supported by grants from The Dr Miriam and Sheldon G. Adelson Medical Research Foundation and the Defense Health Program through the Department of Defense Ovarian Cancer Research Program (Teal Innovator Award No. OC130454/W81XWH-14-1-0385). Opinions, interpretations, conclusions and recommendations presented in this manuscript are those of the author and are not necessarily endorsed by the Department of Defense. The authors also receive funding from The Hodson Trust (S.B.B.), the Commonwealth Foundation (S.B.B. and J.R.B.), the Emerson Cancer Research Award (S.B.B.), the Rising Tide Foundation for Clinical Research (S.B.B. and J.R.B.), the Stand Up To Cancer Jim Toth Sr Breakthrough Prize in Lung Cancer (S.B.B. and J.R.B.), the Van Andel Research Institute through the Van Andel Research Institute–Stand Up To Cancer Epigenetics Dream Team (to S.B.B.; Stand Up To Cancer is a program of the Entertainment Industry Foundation that is administered by AACR), and the NIH National Cancer Institute award number P30CA006973 (SKCCC Core Grant to S.B.B.). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Author information
Authors and Affiliations
Contributions
M.J.T., M.V. and S.B.B. researched data for the article and wrote the manuscript. All authors made substantial contribution to discussions of content and reviewed and/or edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
S.B.B. is an inventor of the methylation-specific PCR platform, which is licensed to MDxHealth in agreement with Johns Hopkins University; S.B.B. and Johns Hopkins University are entitled to royalty sales shares. S.B.B. is on the Scientific Advisory Board for Mirati Therapeutics. J.R.B. is on advisory board/consultant for Amgen, BMS (uncompensated), Celgene, Genentech, Janssen Oncology, Lilly, Merck and Syndax. J.R.B. recieves grant research funding from AstraZeneca/MedImmune, BMS and Merck. K.A.M. is a consultant for AstraZeneca. All other authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Clinical Oncology thanks M. Maio and the other, anonymous, reviewers for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Topper, M.J., Vaz, M., Marrone, K.A. et al. The emerging role of epigenetic therapeutics in immuno-oncology. Nat Rev Clin Oncol 17, 75–90 (2020). https://doi.org/10.1038/s41571-019-0266-5
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41571-019-0266-5
This article is cited by
-
SETDB1 promotes progression through upregulation of SF3B4 expression and regulates the immunity in ovarian cancer
Journal of Ovarian Research (2024)
-
Dual inhibitors of DNMT and HDAC induce viral mimicry to induce antitumour immunity in breast cancer
Cell Death Discovery (2024)
-
The constitutive activation of STAT3 gene and its mutations are at the crossroad between LGL leukemia and autoimmune disorders
Blood Cancer Journal (2024)
-
HDAC6 inhibitor ACY-1215 enhances STAT1 acetylation to block PD-L1 for colorectal cancer immunotherapy
Cancer Immunology, Immunotherapy (2024)
-
Design, synthesis, and in vitro biological evaluation of novel HDAC inhibitors bearing C-1 phenyl substituted tetrahydroisoquinoline Cap moiety as anti-tumor therapeutic agents
Medicinal Chemistry Research (2024)
