Epigenetic Approaches to Boost the Efficacy of CAR T-Cell Therapy in Treating Carcinomas
DOI:
https://doi.org/10.58445/rars.3447Keywords:
CAR T-cell therapy, T-cell exhaustion, Epigenetic modificationsAbstract
Cancer is one of the most common and deadly diseases known to humans. The application of immunotherapies to treat solid tumors (carcinomas) has been a topic of discussion and research. A common limitation seen throughout this development is T-cell exhaustion, which this paper aims to explain, and discuss how this problem can be neutralized using Epigenetic Modifications. Therefore, this paper explores how epigenetic modifications can be leveraged to overcome T-cell exhaustion and enhance the efficacy of CAR T-cell therapy in treating solid tumors. CAR T-cell therapy has already been developed and applied to patients, however it is still a relatively new immunotherapy and has some limitations, especially for the treatment of solid tumors. Overcoming T-cell exhaustion is important because it revives the CAR T-cell therapy from a state of exhaustion, to an active state, allowing to accurately identify and eradicate cancerous cells. There have been significant research studies that have used histone modifications, DNA methylation, demethylation, and acetylation to decrease T-cell exhaustion and improve T-cell treatment. This paper amplifies the importance of leveraging epigenetics to increase the efficiency of T-cell therapy for the treatment of cancers.
References
References
Anderson, Nicole M., and M. Celeste Simon. “Tumor Microenvironment.” Current Biology : CB, vol. 30, no. 16, Aug. 2020, pp. R921–25. PubMed Central, https://doi.org/10.1016/j.cub.2020.06.081.
Angiolilli, Chiara, et al. “The Acetyl Code in Rheumatoid Arthritis and Other Rheumatic Diseases.” Epigenomics, vol. 9, no. 4, Apr. 2017, pp. 447–61. tandfonline.com (Atypon), https://doi.org/10.2217/epi-2016-0136.
Arteaga, Carlos L. “Epidermal Growth Factor Receptor Dependence in Human Tumors: More Than Just Expression?” The Oncologist, vol. 7, no. S4, Aug. 2002, pp. 31–39. Silverchair, https://doi.org/10.1634/theoncologist.7-suppl_4-31.
Bannister, Andrew J., and Tony Kouzarides. “Regulation of Chromatin by Histone Modifications.” Cell Research, vol. 21, no. 3, Mar. 2011, pp. 381–95. www.nature.com, https://doi.org/10.1038/cr.2011.22.
Blank, Christian U., et al. “Defining ‘T Cell Exhaustion.’” Nature Reviews Immunology, vol. 19, no. 11, Nov. 2019, pp. 665–74. www.nature.com, https://doi.org/10.1038/s41577-019-0221-9.
Budimir, Natalija, et al. “Reversing T-Cell Exhaustion in Cancer: Lessons Learned from PD-1/PD-L1 Immune Checkpoint Blockade.” Cancer Immunology Research, vol. 10, no. 2, Feb. 2022, pp. 146–53. PubMed, https://doi.org/10.1158/2326-6066.CIR-21-0515.
CAR T Cells: Engineering Immune Cells to Treat Cancer - NCI. cgvArticle. 6 Dec. 2013, nciglobal,ncienterprise, https://www.cancer.gov/about-cancer/treatment/research/car-t-cells.
Castelletti, Laura, et al. “Anti-Mesothelin CAR T Cell Therapy for Malignant Mesothelioma.” Biomarker Research, vol. 9, Feb. 2021, p. 11. PubMed Central, https://doi.org/10.1186/s40364-021-00264-1.
Catakovic, Kemal, et al. “T Cell Exhaustion: From Pathophysiological Basics to Tumor Immunotherapy.” Cell Communication and Signaling, vol. 15, no. 1, Jan. 2017, p. 1. BioMed Central, https://doi.org/10.1186/s12964-016-0160-z.
Ceccacci, Elena, and Saverio Minucci. “Inhibition of Histone Deacetylases in Cancer Therapy: Lessons from Leukaemia.” British Journal of Cancer, vol. 114, no. 6, Mar. 2016, pp. 605–11. www.nature.com, https://doi.org/10.1038/bjc.2016.36.
Clevealand, Clinic. “What Are Cytokines? Types and Function.” Cleveland Clinic, https://my.clevelandclinic.org/health/body/24585-cytokines. Accessed 2 Jan. 2025.
Cliff, Edward R. Scheffer, et al. “High Cost of Chimeric Antigen Receptor T-Cells: Challenges and Solutions.” American Society of Clinical Oncology Educational Book, no. 43, July 2023, p. e397912. ascopubs.org (Atypon), https://doi.org/10.1200/EDBK_397912.
Daei Sorkhabi, Amin, et al. “The Current Landscape of CAR T-Cell Therapy for Solid Tumors: Mechanisms, Research Progress, Challenges, and Counterstrategies.” Frontiers in Immunology, vol. 14, Mar. 2023, p. 1113882. PubMed Central, https://doi.org/10.3389/fimmu.2023.1113882.
Dutta, Avik, et al. “New Insights into Epigenetic Regulation of T Cell Differentiation.” Cells, vol. 10, no. 12, Dec. 2021, p. 3459. PubMed Central, https://doi.org/10.3390/cells10123459.
Esfahani, K., et al. “A Review of Cancer Immunotherapy: From the Past, to the Present, to the Future.” Current Oncology, vol. 27, no. Suppl 2, Apr. 2020, pp. S87–97. PubMed Central, https://doi.org/10.3747/co.27.5223.
Fierz, Beat, and Tom W. Muir. “Chromatin as an Expansive Canvas for Chemical Biology.” Nature Chemical Biology, vol. 8, no. 5, May 2012, pp. 417–27. www.nature.com, https://doi.org/10.1038/nchembio.938.
Ford, B. Rhodes, et al. “Tumor Microenvironmental Signals Reshape Chromatin Landscapes to Limit the Functional Potential of Exhausted T Cells.” Science Immunology, vol. 7, no. 74, Aug. 2022, p. eabj9123. PubMed Central, https://doi.org/10.1126/sciimmunol.abj9123.
Gabrilovich, Dmitry I., and Srinivas Nagaraj. “Myeloid-Derived Suppressor Cells as Regulators of the Immune System.” Nature Reviews Immunology, vol. 9, no. 3, Mar. 2009, pp. 162–74. www.nature.com, https://doi.org/10.1038/nri2506.
Gross, G, et al. “Expression of Immunoglobulin-T-Cell Receptor Chimeric Molecules as Functional Receptors with Antibody-Type Specificity.” Proceedings of the National Academy of Sciences, vol. 86, no. 24, Dec. 1989, pp. 10024–28. pnas.org (Atypon), https://doi.org/10.1073/pnas.86.24.10024.
Harb, Hani, et al. “Recent Developments in Epigenetics of Pediatric Asthma.” Current Opinion in Pediatrics, vol. 28, no. 6, Dec. 2016, p. 754. journals.lww.com, https://doi.org/10.1097/MOP.0000000000000424.
Histone H3 Phosphorylation, Immediate-Early Gene Expression, and the Nucleosomal Response: A Historical Perspective 1This Article Is Part of Special Issue Entitled Asilomar Chromatin and Has Undergone the Journal’s Usual Peer Review Process. https://cdnsciencepub.com/doi/10.1139/o11-092. Accessed 20 Apr. 2025.
Huang, Shengkang, et al. “Deciphering and Advancing CAR T-Cell Therapy with Single-Cell Sequencing Technologies.” Molecular Cancer, vol. 22, no. 1, May 2023, p. 80. BioMed Central, https://doi.org/10.1186/s12943-023-01783-1.
Hudecek, Michael, et al. “The Nonsignaling Extracellular Spacer Domain of Chimeric Antigen Receptors Is Decisive for In Vivo Antitumor Activity.” Cancer Immunology Research, vol. 3, no. 2, Feb. 2015, pp. 125–35. Silverchair, https://doi.org/10.1158/2326-6066.CIR-14-0127.
Ito, Yusuke, et al. “Gene Editing Technology to Improve Antitumor T-Cell Functions in Adoptive Immunotherapy.” Inflammation and Regeneration, vol. 44, no. 1, Mar. 2024, p. 13. BioMed Central, https://doi.org/10.1186/s41232-024-00324-7.
Jensen, Michael C, and Stanley R Riddell. “Designing Chimeric Antigen Receptors to Effectively and Safely Target Tumors.” Current Opinion in Immunology, Lymphocyte development and activation * Tumour immunology, vol. 33, Apr. 2015, pp. 9–15. ScienceDirect, https://doi.org/10.1016/j.coi.2015.01.002.
Kakarla, Sunitha, and Stephen Gottschalk. “CAR T Cells for Solid Tumors: Armed and Ready to Go?” Cancer Journal (Sudbury, Mass.), vol. 20, no. 2, 2014, pp. 151–55. PubMed Central, https://doi.org/10.1097/PPO.0000000000000032.
Milone, Michael C., et al. “Chimeric Receptors Containing CD137 Signal Transduction Domains Mediate Enhanced Survival of T Cells and Increased Antileukemic Efficacy In Vivo.” Molecular Therapy, vol. 17, no. 8, Aug. 2009, pp. 1453–64. www.cell.com, https://doi.org/10.1038/mt.2009.83.
National Library of Medicine, National Cancer Insitute. Definition of Macrophage - NCI Dictionary of Cancer Terms - NCI. nciAppModulePage. 2 Feb. 2011, nciglobal,ncienterprise, https://www.cancer.gov/publications/dictionaries/cancer-terms/def/macrophage.
Nazha, Bassel, et al. “Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy.” Frontiers in Oncology, vol. 10, July 2020, p. 1000. PubMed Central, https://doi.org/10.3389/fonc.2020.01000.
Odorizzi, Pamela, and E. John Wherry. “Inhibitory Receptors on Lymphocytes: Insights from Infections.” Journal of Immunology (Baltimore, Md. : 1950), vol. 188, no. 7, Apr. 2012, pp. 2957–65. PubMed Central, https://doi.org/10.4049/jimmunol.1100038.
Onodera, Atsushi, et al. “Menin Controls the Memory Th2 Cell Function by Maintaining the Epigenetic Integrity of Th2 Cells.” The Journal of Immunology, vol. 199, no. 3, Aug. 2017, pp. 1153–62. Silverchair, https://doi.org/10.4049/jimmunol.1602129.
O’Shea, John J., et al. “9 - Cytokines and Cytokine Receptors.” Clinical Immunology (Fourth Edition), edited by Robert R. Rich et al., Elsevier, 2013, pp. 108–35. ScienceDirect, https://doi.org/10.1016/B978-0-7234-3691-1.00033-7.
Petty, Emily, and Lorraine Pillus. “Balancing Chromatin Remodeling and Histone Modifications in Transcription.” Trends in Genetics : TIG, vol. 29, no. 11, Nov. 2013, pp. 621–29. PubMed Central, https://doi.org/10.1016/j.tig.2013.06.006.
Ramos, Carlos A., et al. “In Vivo Fate and Activity of Second- versus Third-Generation CD19-Specific CAR-T Cells in B Cell Non-Hodgkin’s Lymphomas.” Molecular Therapy, vol. 26, no. 12, Dec. 2018, pp. 2727–37. www.cell.com, https://doi.org/10.1016/j.ymthe.2018.09.009.
Robbins, Paul F., et al. “A Pilot Trial Using Lymphocytes Genetically Engineered with an NY-ESO-1-Reactive T Cell Receptor: Long Term Follow up and Correlates with Response.” Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, vol. 21, no. 5, Mar. 2015, pp. 1019–27. PubMed Central, https://doi.org/10.1158/1078-0432.CCR-14-2708.
Rocha, Gabriel Iudy Yamaguchi, et al. “Epigenome-Driven Strategies for Personalized Cancer Immunotherapy.” Cancer Management and Research, vol. 15, Dec. 2023, pp. 1351–67. PubMed Central, https://doi.org/10.2147/CMAR.S272031.
Rodriguez-Garcia, Alba, et al. “CAR-T Cell-Mediated Depletion of Immunosuppressive Tumor-Associated Macrophages Promotes Endogenous Antitumor Immunity and Augments Adoptive Immunotherapy.” Nature Communications, vol. 12, Feb. 2021, p. 877. PubMed Central, https://doi.org/10.1038/s41467-021-20893-2.
Rossetto, Dorine, et al. “Histone Phosphorylation: A Chromatin Modification Involved in Diverse Nuclear Events.” Epigenetics, vol. 7, no. 10, Oct. 2012, pp. 1098–108. Taylor and Francis+NEJM, https://doi.org/10.4161/epi.21975.
Saitakis, Michael. “Epigenetic Reprogramming of CAR T Cells for in Vivo Functional Persistence against Solid Tumors.” Genes & Immunity, Feb. 2024, pp. 1–3. www.nature.com, https://doi.org/10.1038/s41435-024-00262-x.
Sawicka, Anna, and Christian Seiser. “Histone H3 Phosphorylation – A Versatile Chromatin Modification for Different Occasions.” Biochimie, Special Section on Epigenetics, vol. 94, no. 11, Nov. 2012, pp. 2193–201. ScienceDirect, https://doi.org/10.1016/j.biochi.2012.04.018.
Scheer, Sebastian, et al. “The Methyltransferase DOT1L Controls Activation and Lineage Integrity in CD4+ T Cells during Infection and Inflammation.” Cell Reports, vol. 33, no. 11, Dec. 2020. www.cell.com, https://doi.org/10.1016/j.celrep.2020.108505.
Schuettengruber, Bernd, et al. “Trithorax Group Proteins: Switching Genes on and Keeping Them Active.” Nature Reviews Molecular Cell Biology, vol. 12, no. 12, Dec. 2011, pp. 799–814. www.nature.com, https://doi.org/10.1038/nrm3230.
Sterner, Robert C., and Rosalie M. Sterner. “CAR-T Cell Therapy: Current Limitations and Potential Strategies.” Blood Cancer Journal, vol. 11, no. 4, Apr. 2021, pp. 1–11. www.nature.com, https://doi.org/10.1038/s41408-021-00459-7.
Swygert, Sarah G., and Craig L. Peterson. “Chromatin Dynamics: Interplay between Remodeling Enzymes and Histone Modifications.” Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Molecular mechanisms of histone modification function, vol. 1839, no. 8, Aug. 2014, pp. 728–36. ScienceDirect, https://doi.org/10.1016/j.bbagrm.2014.02.013.
Tang, Careen K., et al. “Epidermal Growth Factor Receptor vIII Enhances Tumorigenicity in Human Breast Cancer1.” Cancer Research, vol. 60, no. 11, June 2000, pp. 3081–87. Silverchair.
Tang, Xiao-Yi, et al. “Third-Generation CD28/4-1BB Chimeric Antigen Receptor T Cells for Chemotherapy Relapsed or Refractory Acute Lymphoblastic Leukaemia: A Non-Randomised, Open-Label Phase I Trial Protocol.” BMJ Open, vol. 6, no. 12, Dec. 2016, p. e013904. Haematology (Incl Blood Transfusion). bmjopen.bmj.com, https://doi.org/10.1136/bmjopen-2016-013904.
Tu, Wen Juan, et al. “Targeting Nuclear LSD1 to Reprogram Cancer Cells and Reinvigorate Exhausted T Cells via a Novel LSD1-EOMES Switch.” Frontiers in Immunology, vol. 11, June 2020, p. 1228. PubMed Central, https://doi.org/10.3389/fimmu.2020.01228.
Wang, Chao, et al. “Loss of the Signaling Adaptor TRAF1 Causes CD8+ T Cell Dysregulation during Human and Murine Chronic Infection.” The Journal of Experimental Medicine, vol. 209, no. 1, Jan. 2012, pp. 77–91. PubMed Central, https://doi.org/10.1084/jem.20110675.
Wang, Yufei, et al. “Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy.” Cancers, vol. 12, no. 9, Sept. 2020, p. 2626. PubMed Central, https://doi.org/10.3390/cancers12092626.
Wapenaar, Hannah, and Frank J. Dekker. “Histone Acetyltransferases: Challenges in Targeting Bi-Substrate Enzymes.” Clinical Epigenetics, vol. 8, no. 1, May 2016, p. 59. BioMed Central, https://doi.org/10.1186/s13148-016-0225-2.
Wherry, E. John. “T Cell Exhaustion.” Nature Immunology, vol. 12, no. 6, June 2011, pp. 492–99. www.nature.com, https://doi.org/10.1038/ni.2035.
Wherry, E. John, and Makoto Kurachi. “Molecular and Cellular Insights into T Cell Exhaustion.” Nature Reviews. Immunology, vol. 15, no. 8, Aug. 2015, pp. 486–99. PubMed Central, https://doi.org/10.1038/nri3862.
Yang, Xuguang, et al. “FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling.” Cancer Research, vol. 76, no. 14, July 2016, pp. 4124–35. PubMed, https://doi.org/10.1158/0008-5472.CAN-15-2973.
Yin, Mingzhu, et al. “Tumor-Associated Macrophages Drive Spheroid Formation during Early Transcoelomic Metastasis of Ovarian Cancer.” The Journal of Clinical Investigation, vol. 126, no. 11, pp. 4157–73. PubMed Central, https://doi.org/10.1172/JCI87252.
Zamarron, Brian F., and WanJun Chen. “Dual Roles of Immune Cells and Their Factors in Cancer Development and Progression.” International Journal of Biological Sciences, vol. 7, no. 5, May 2011, pp. 651–58. PubMed Central.
Zebley, Caitlin C., et al. “CD19-CAR T Cells Undergo Exhaustion DNA Methylation Programming in Patients with Acute Lymphoblastic Leukemia.” Cell Reports, vol. 37, no. 9, Nov. 2021. www.cell.com, https://doi.org/10.1016/j.celrep.2021.110079.
Zhang, Biao, et al. “CD8+ T Cell Exhaustion and Its Regulatory Mechanisms in the Tumor Microenvironment: Key to the Success of Immunotherapy.” Frontiers in Immunology, vol. 15, Sept. 2024, p. 1476904. pmc.ncbi.nlm.nih.gov, https://doi.org/10.3389/fimmu.2024.1476904.
Zhang, Ge, et al. “Anti-Melanoma Activity of T Cells Redirected with a TCR-like Chimeric Antigen Receptor.” Scientific Reports, vol. 4, no. 1, Jan. 2014, p. 3571. www.nature.com, https://doi.org/10.1038/srep03571.
Zhang, Zhen, et al. “T Cell Dysfunction and Exhaustion in Cancer.” Frontiers in Cell and Developmental Biology, vol. 8, Feb. 2020, p. 17. pmc.ncbi.nlm.nih.gov, https://doi.org/10.3389/fcell.2020.00017.
Zhao, Yangjing, et al. “Exhaustion and Senescence: Two Crucial Dysfunctional States of T Cells in the Tumor Microenvironment.” Cellular and Molecular Immunology, vol. 17, no. 1, Dec. 2019, p. 27. pmc.ncbi.nlm.nih.gov, https://doi.org/10.1038/s41423-019-0344-8.
Downloads
Posted
Categories
License
Copyright (c) 2025 Utkarsh Vishwanathan
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
