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Reddy KD, Xenaki D, Adcock IM, Oliver BGG, Zakarya R. Epigenetic Inhibitors Differentially Impact TGF-β1 Signaling Cascades in COPD Airway Smooth Muscle Cells. Cells 2024; 14:31. [PMID: 39791732 PMCID: PMC11720536 DOI: 10.3390/cells14010031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/18/2024] [Accepted: 12/27/2024] [Indexed: 01/12/2025] Open
Abstract
Background: Chronic obstructive pulmonary disease (COPD) is characterized by progressive and incurable airflow obstruction and chronic inflammation. Both TGF-β1 and CXCL8 have been well described as fundamental to COPD progression. DNA methylation and histone acetylation, which are well-understood epigenetic mechanisms regulating gene expression, are associated with COPD progression. However, a deeper understanding of the complex mechanisms associated with DNA methylation, histone post-translational changes and RNA methylation in the context of regulatory pathways remains to be elucidated. We here report on how DNA methylation and histone acetylation inhibition differentially affect CXCL8 signaling in primary human non-COPD and COPD airway cells. Methods: Airway smooth muscle (ASM) cells, a pivotal cell type in COPD, were isolated from the small airways of heavy smokers with and without COPD. Histone acetylation and DNA methylation were inhibited before the TGF-β1 stimulation of cells. Subsequently, CXCL8 production and the abundance and activation of pertinent transcription regulatory proteins (NF-κB, p38 MAPK and JNK) were analyzed. Results: TGF-β1-stimulated CXCL8 release from ASM cells from 'healthy' smoker subjects was significantly modulated by DNA methylation (56.32 pg/mL and 56.60 pg/mL) and acetylation inhibitors (27.50 pg/mL and 48.85 pg/mL) at 24 and 48 h, respectively. However, modulation via the inhibition of DNA methylation (34.06 pg/mL and 43.18 pg/mL) and acetylation (23.14 pg/mL and 27.18 pg/mL) was observed to a lesser extent in COPD ASM cells. These changes were associated with differences in the TGF-β1 activation of NF-κB and MAPK pathways at 10 and 20 min. Conclusions: Our findings offer insight into differential epigenetics in controlling COPD ASM cells and provide a foundation warranting future studies on epigenetic differences associated with COPD diagnosis. This would provide a scope for developing therapeutic interventions targeting signaling and epigenetic pathways to improve patient outcomes.
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Affiliation(s)
- Karosham Diren Reddy
- Respiratory Cellular and Molecular Biology Group, Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, Sydney, NSW 2113, Australia; (D.X.); (B.G.G.O.)
- School of Life Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Dikaia Xenaki
- Respiratory Cellular and Molecular Biology Group, Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, Sydney, NSW 2113, Australia; (D.X.); (B.G.G.O.)
| | - Ian M. Adcock
- Airways Disease, Respiratory Cell & Molecular Biology, Airways Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2BX, UK;
| | - Brian G. G. Oliver
- Respiratory Cellular and Molecular Biology Group, Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, Sydney, NSW 2113, Australia; (D.X.); (B.G.G.O.)
- School of Life Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Razia Zakarya
- School of Life Science, University of Technology Sydney, Ultimo, NSW 2007, Australia
- Epigenetics of Chronic Disease Group, Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, Sydney, NSW 2113, Australia
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Stefan VE, Weber DD, Lang R, Kofler B. Overcoming immunosuppression in cancer: how ketogenic diets boost immune checkpoint blockade. Cancer Immunol Immunother 2024; 74:23. [PMID: 39537934 PMCID: PMC11561221 DOI: 10.1007/s00262-024-03867-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024]
Abstract
Immune checkpoint blockade (ICB) is now part of the standard of care in the treatment of many forms of cancer, yet it lacks efficacy in some patients, necessitating adjunct therapies to support the anti-tumor immune response. Ketogenic diets (KDs), i.e., high-fat low-carbohydrate diets, have been shown to have antiproliferative and immunomodulatory effects in various preclinical cancer studies. Here, we review current knowledge of the complex interplay of KDs and the anti-tumor immune response in the context of ICB therapy, to update our understanding of diet-induced immunometabolic reprogramming in cancer. Preclinical cancer studies have revealed increased activation of and infiltration by tumor-fighting immune cells, especially CD8+ T cells, but also M1 macrophages and natural killer cells, in response to a KD regimen. In contrast, immune-suppressive cells such as regulatory CD4+ T lymphocytes, M2 macrophages, and myeloid-derived suppressor cells were reported to be decreased or largely unaffected in tumors of KD-fed mice. KDs also showed synergism with ICB therapy in several preclinical tumor studies. The observed effects are ascribed to the ability of KDs to improve immune cell infiltration and induce downregulation of immune-inhibitory processes, thus creating a more immunogenic tumor microenvironment. The studies reviewed herein show that altering the metabolic composition of the tumor microenvironment by a KD can boost the anti-tumor immune response and diminish even immunotherapy-resistant as well as immunologically "cold" tumors. However, the exact underlying mechanisms remain to be elucidated, requiring further studies before KDs can be successfully implemented as an adjunct tumor therapy to improve survival rates for cancer patients.
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Affiliation(s)
- Victoria E Stefan
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
- Department of Biosciences and Medical Biology, University of Salzburg, Salzburg, Austria
| | - Daniela D Weber
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Roland Lang
- Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria.
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Yi JM. Epigenetic regulation of HERVs: Implications for cancer immunotherapy. Genes Genomics 2024; 46:1303-1312. [PMID: 39088189 DOI: 10.1007/s13258-024-01546-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 07/07/2024] [Indexed: 08/02/2024]
Abstract
BACKGROUND Human endogenous retroviruses (HERVs), integrated into the human genome during primate evolution, constitute approximately 8% of the human genome. Although most HERVs are non-protein-coding owing to mutations, insertions, deletions, and truncations, recent research has revealed their diverse roles in biological processes, including disease pathogenesis. OBJECTIVE Although many HERVs remain inactive, they have been implicated in various diseases, particularly cancer, prompting an increased interest in harnessing HERVs for therapeutic purposes. This review explores the recent advancements in our understanding of the biological roles of HERVs, emphasizing their clinical relevance in cancer treatment. METHODS Here, we discuss how the detection of transposable elements (TEs), including HERVs, by the immune system triggers innate immune responses in human cancers. CONCLUSION Additionally, we outline recent progress in elucidating the implications of HERV activation in cancer and how targeting HERVs holds promise for anti-cancer treatments by modulating epigenetic plasticity and disrupting cancer initiation and progression.
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Affiliation(s)
- Joo Mi Yi
- Department of Microbiology and Immunology, College of Medicine, Inje University, Busan, 47392, South Korea.
- Department of Medical & Molecular Genetics, Indiana University School of Medicine, Bloomington, IN, 47405, USA.
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4
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Murphy S, Rahmy S, Gan D, Liu G, Zhu Y, Manyak M, Duong L, He J, Schofield JH, Schafer ZT, Li J, Lu X, Lu X. Ketogenic Diet Alters the Epigenetic and Immune Landscape of Prostate Cancer to Overcome Resistance to Immune Checkpoint Blockade Therapy. Cancer Res 2024; 84:1597-1612. [PMID: 38588411 PMCID: PMC11096030 DOI: 10.1158/0008-5472.can-23-2742] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 01/15/2024] [Accepted: 03/12/2024] [Indexed: 04/10/2024]
Abstract
Resistance to immune checkpoint blockade (ICB) therapy represents a formidable clinical challenge limiting the efficacy of immunotherapy. In particular, prostate cancer poses a challenge for ICB therapy due to its immunosuppressive features. A ketogenic diet (KD) has been reported to enhance response to ICB therapy in some other cancer models. However, adverse effects associated with continuous KD were also observed, demanding better mechanistic understanding and optimized regimens for using KD as an immunotherapy sensitizer. In this study, we established a series of ICB-resistant prostate cancer cell lines and developed a highly effective strategy of combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic KD (CKD), or dietary supplementation of the ketone body β-hydroxybutyrate (BHB), which is an endogenous HDACi. CKD and BHB supplementation each delayed prostate cancer tumor growth as monotherapy, and both BHB and adaptive immunity were required for the antitumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that HDACi and ketogenesis enhanced ICB efficacy through both cancer cell-intrinsic mechanisms, including upregulation of MHC class I molecules, and -extrinsic mechanisms, such as CD8+ T-cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen-presenting cells, and diminished neutrophil infiltration. Overall, these findings illuminate a potential clinical path of using HDACi and optimized KD regimens to enhance ICB therapy for prostate cancer. SIGNIFICANCE Optimized cyclic ketogenic diet and 1,3-butanediol supplementation regimens enhance the efficacy of immune checkpoint blockade in prostate cancer through epigenetic and immune modulations, providing dietary interventions to sensitize tumors to immunotherapy.
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Affiliation(s)
- Sean Murphy
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Sharif Rahmy
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Dailin Gan
- Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Guoqiang Liu
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Yini Zhu
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Maxim Manyak
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Loan Duong
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Jianping He
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - James H Schofield
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Zachary T Schafer
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Jun Li
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA
- Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Xuemin Lu
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Xin Lu
- Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA
- Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA
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Murphy S, Rahmy S, Gan D, Zhu Y, Manyak M, Li J, Lu X, Lu X. Overcome Prostate Cancer Resistance to Immune Checkpoint Therapy with Ketogenic Diet-Induced Epigenetic Reprogramming. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.07.552383. [PMID: 37609341 PMCID: PMC10441324 DOI: 10.1101/2023.08.07.552383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
Advanced prostate cancer (PCa) is overwhelmingly resistant to immune checkpoint blockade (ICB) therapy, representing a formidable clinical challenge. In this study, we developed a syngeneic murine PCa model with acquired ICB resistance. Using this model, synergistic efficacy was achieved by combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic ketogenic diet (CKD), or supplementation of ketone body β-hydroxybutyrate (BHB, endogenous HDACi) via 1,3-butanediol-admixed food. CKD and BHB supplementation delayed PCa tumors as monotherapy, and both BHB and adaptive immunity are required for the anti-tumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that the HDACi and ketogenesis-enhanced ICB therapy involves cancer-cell-intrinsic (upregulated MHC class I molecules) and extrinsic mechanisms (CD8 + T cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen presenting cells, and diminished neutrophils). Overall, these findings underscore the potential of using HDACi and optimized KD to enhance ICB therapy for PCa.
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Li LJ, Zhang JY. Treatment of refractory/relapsed extranodal NK/T cell lymphoma with decitabine plus anti-PD-1: A case report. World J Clin Cases 2022; 10:10193-10200. [PMID: 36246799 PMCID: PMC9561561 DOI: 10.12998/wjcc.v10.i28.10193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/24/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Extranodal natural killer/T cell lymphoma, nasal type (ENKL) is a highly aggressive malignancy characterized by its association with Epstein-Barr virus (EBV) and extranodal involvement, which shows a poor clinical outcome. Although L-asparaginase-based chemotherapy has improved the response rates of relapsed/refractory (R/R) ENKL, relapse occurs in up to 50% of patients with disseminated disease.
CASE SUMMARY Immune evasion has emerged as a critical pathway for survival in ENKL and may be effectuated via STAT3-driven upregulation of programmed cell death ligand 1 (PD-L1) or other molecular pathways. Anti-PD-1 is effective for R/R ENKL with EBV-driven upregulation of PD-L1 expression. Anti-PD-1 combined with decitabine showed positive preliminary results in a patient with R/R ENKL and resistance to anti-PD-1.
CONCLUSION The treatment experience, in this case, demonstrated the potential ability of decitabine combined with PD-1 inhibitor to treat R/R ENKL, thus providing a new treatment strategy for this tumor.
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Affiliation(s)
- Lin-Jie Li
- Department of Hematology, Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China
| | - Jun-Yu Zhang
- Department of Hematology, Lishui Municipal Central Hospital, Lishui 323000, Zhejiang Province, China
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Insights into the therapeutic potential of histone deacetylase inhibitor/immunotherapy combination regimens in solid tumors. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2022; 24:1262-1273. [PMID: 35066777 DOI: 10.1007/s12094-022-02779-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 12/31/2021] [Indexed: 12/27/2022]
Abstract
Solid tumors including skin, lung, breast, colon, and prostate cancers comprise the most diagnosed cancers worldwide. Treatment of such cancers is still challenging specially in the advanced/metastatic setting. The growing understanding of the tumor microenvironment has revolutionized the cancer therapy paradigms. Targeting programmed death-1 (PD-1)/PD-L1 immune checkpoint has been extensively studied over this decade as a new trend in the management of hard-to-treat cancers by harnessing the power of the immune system to eradicate the tumors. Yet, low response rate and resistance were observed when immunotherapies were tested as monotherapy. This urged the need to develop combinatorial regimens of immunotherapy with other immune modulatory agents to enhance its therapeutic potential and help in reverting the resistance. Epigenetic modifiers such as histone deacetylase inhibitors (HDACIs) showed favorable effects on modulating the tumor microenvironment along with the host immune cells. This qualified HDACIs as an attractive candidate class to be tested in combination with immunotherapy. In this review we cover the ongoing clinical trials that investigate the safety and/or the efficacy of HDACI/immunotherapy combinations in solid tumors including skin cancer, prostate cancer, breast cancer, colorectal cancer, lung cancer and recapitulates areas for future research.
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Wu SY, Xie ZY, Yan LY, Liu XF, Zhang Y, Wang DA, Dong J, Sun HT. The correlation of EZH2 expression with the progression and prognosis of hepatocellular carcinoma. BMC Immunol 2022; 23:28. [PMID: 35659256 PMCID: PMC9166340 DOI: 10.1186/s12865-022-00502-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 05/24/2022] [Indexed: 12/24/2022] Open
Abstract
Background Enhancer of Zeste homologue 2 (EZH2) is a polycomb group gene and an epigenetic regulator that inhibits transcription, a modification associated with gene silencing. EZH2 plays an essential role in humoral and cell-mediated adaptive immunity. The purpose of the current study is to investigate the prognostic potential of EZH2 and to comprehensively analyse the correlation between EZH2 and immune infiltration in multiple cancer cases, especially liver hepatocellular carcinoma. Methods EZH2 expression across cancers was explored through Oncomine, HPA, and GEPIA2. Additionally, the prognostic value of EZH2 analysis across cancers was based on the GEPIA2, TCGA portal, Kaplan–Meier Plotter, and LOGpc databases. Based on GO and KEGG analyses, GSEA helped demonstrate the biological processes through which EZH2 might lead to HCC development. GEPIA and TIMER were adopted to detect the possible relationship of EZH2 expression with tumour-infiltrating immune cells (TIICs). Results EZH2 overexpression levels were associated with poor prognosis of cancer, especially hepatocellular carcinoma. A high EZH2 expression level is related to a poor prognosis of HCC, especially in disease histology and stage III. The EZH2 expression level was positively correlated with critical gene markers of TAMs, M2 macrophages, M1 macrophages, and monocytes. Further analysis revealed that EZH2 genes were mainly related to DNA recombination, mitotic cell cycle phase transition, and chromosome segregation. Conclusion EZH2 plays an essential role in the immune microenvironment and is a potential prognostic marker and immunotherapy target for hepatocellular carcinoma. Supplementary Information The online version contains supplementary material available at 10.1186/s12865-022-00502-7.
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Liu Z, Ren Y, Weng S, Xu H, Li L, Han X. A New Trend in Cancer Treatment: The Combination of Epigenetics and Immunotherapy. Front Immunol 2022; 13:809761. [PMID: 35140720 PMCID: PMC8818678 DOI: 10.3389/fimmu.2022.809761] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/03/2022] [Indexed: 12/15/2022] Open
Abstract
In recent years, immunotherapy has become a hot spot in the treatment of tumors. As an emerging treatment, it solves many problems in traditional cancer treatment and has now become the main method for cancer treatment. Although immunotherapy is promising, most patients do not respond to treatment or develop resistance. Therefore, in order to achieve a better therapeutic effect, combination therapy has emerged. The combination of immune checkpoint inhibition and epigenetic therapy is one such strategy. In this review, we summarize the current understanding of the key mechanisms of how epigenetic mechanisms affect cancer immune responses and reveal the key role of epigenetic processes in regulating immune cell function and mediating anti-tumor immunity. In addition, we highlight the outlook of combined epigenetic and immune regimens, particularly the combination of immune checkpoint blockade with epigenetic agents, to address the limitations of immunotherapy alone.
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Affiliation(s)
- Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Interventional Institute of Zhengzhou University, Zhengzhou, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Yuqing Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Siyuan Weng
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Interventional Institute of Zhengzhou University, Zhengzhou, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Hui Xu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Interventional Institute of Zhengzhou University, Zhengzhou, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Lifeng Li
- Internet Medical and System Applications of National Engineering Laboratory, Zhengzhou, China
- Medical School, Huanghe Science and Technology University, Zhengzhou, China
- *Correspondence: Xinwei Han, ; Lifeng Li,
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Interventional Institute of Zhengzhou University, Zhengzhou, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
- *Correspondence: Xinwei Han, ; Lifeng Li,
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Jansz N, Faulkner GJ. Endogenous retroviruses in the origins and treatment of cancer. Genome Biol 2021; 22:147. [PMID: 33971937 PMCID: PMC8108463 DOI: 10.1186/s13059-021-02357-4] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/21/2021] [Indexed: 02/07/2023] Open
Abstract
Endogenous retroviruses (ERVs) are emerging as promising therapeutic targets in cancer. As remnants of ancient retroviral infections, ERV-derived regulatory elements coordinate expression from gene networks, including those underpinning embryogenesis and immune cell function. ERV activation can promote an interferon response, a phenomenon termed viral mimicry. Although ERV expression is associated with cancer, and provisionally with autoimmune and neurodegenerative diseases, ERV-mediated inflammation is being explored as a way to sensitize tumors to immunotherapy. Here we review ERV co-option in development and innate immunity, the aberrant contribution of ERVs to tumorigenesis, and the wider biomedical potential of therapies directed at ERVs.
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Affiliation(s)
- Natasha Jansz
- Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, QLD, 4102, Australia.
| | - Geoffrey J Faulkner
- Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, QLD, 4102, Australia. .,Queensland Brain Institute, University of Queensland, Brisbane, QLD, 4072, Australia.
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11
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Liu Y, Wang C, Li X, Dong L, Yang Q, Chen M, Shi F, Brock M, Liu M, Mei Q, Liu J, Nie J, Han W. Improved clinical outcome in a randomized phase II study of anti-PD-1 camrelizumab plus decitabine in relapsed/refractory Hodgkin lymphoma. J Immunother Cancer 2021; 9:jitc-2021-002347. [PMID: 33820822 PMCID: PMC8025784 DOI: 10.1136/jitc-2021-002347] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2021] [Indexed: 12/14/2022] Open
Abstract
Background Programmed death-1 (PD-1) blockade monotherapy induced durable remission in a subset of patients with relapsed/refractory classical Hodgkin lymphoma (cHL). We asked whether the anti-PD-1 agent, camrelizumab, combined with the DNA demethylating agent, decitabine, improves progression-free survival (PFS) in patients with relapsed/refractory cHL over camrelizumab alone. Methods This extended follow-up of an ongoing randomized phase II trial analyzed PFS among patients enrolled from January 2017 through July 2018. Sixty-one patients with relapsed/refractory cHL who were clinically naïve to PD-1 blockade and had received ≥2 previous therapies were randomized 1:2 to receive either camrelizumab (200 mg) monotherapy or camrelizumab (200 mg, day 8) combined with decitabine (10 mg/day, days 1–5) every 3 weeks. Results With a median follow-up of 34.5 months, complete remission was 79% (95% CI 63% to 90%) in the decitabine-plus-camrelizumab group versus 32% (95% CI 13% to 57%) in the camrelizumab group (p=0.001). Median duration of response was not reached in the decitabine-plus-camrelizumab group, with an estimated 63% (95% CI 46% to 75%) of patients maintaining a response at 24 months. Median PFS with decitabine-plus-camrelizumab therapy was 35.0 months (95% CI not reached) and 15.5 months (95% CI 8.4 to 22.7 months) with camrelizumab monotherapy (HR, 0.46; 95% CI 0.21 to 1.01; p=0.02). Female gender, lower tumor burden, and fewer previous therapies were favorable prognostic factors for durable remission with camrelizumab monotherapy. The PFS benefits of decitabine-plus-camrelizumab versus camrelizumab were observed in most subgroups, especially in patients with relative larger tumor burdens and those treated with ≥3 prior therapies. After decitabine-plus-camrelizumab treatment, the percentage increase of circulating peripheral central memory T-cells correlated with both improved clinical response and PFS, suggesting a putative biomarker of decitabine-plus-camrelizumab therapy for cHL. Conclusions Decitabine-plus-camrelizumab results in longer PFS compared with camrelizumab alone in patients with relapsed/refractory cHL. Trial registration numbers NCT02961101 and NCT03250962.
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Affiliation(s)
- Yang Liu
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Chunmeng Wang
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Xiang Li
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Liang Dong
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Qingming Yang
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Meixia Chen
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Fengxia Shi
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Malcolm Brock
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Miao Liu
- Department of Statistics and Epidemiology, Chinese PLA General Hospital, Beijing, China
| | - Qian Mei
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Jiejie Liu
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Jing Nie
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Weidong Han
- Department of Bio-therapeutic, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
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Wang C, Liu Y, Dong L, Li X, Yang Q, Brock MV, Mei Q, Liu J, Chen M, Shi F, Liu M, Nie J, Han W. Efficacy of Decitabine plus Anti-PD-1 Camrelizumab in Patients with Hodgkin Lymphoma Who Progressed or Relapsed after PD-1 Blockade Monotherapy. Clin Cancer Res 2021; 27:2782-2791. [PMID: 33674274 DOI: 10.1158/1078-0432.ccr-21-0133] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/17/2021] [Accepted: 03/02/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Programmed death-1 (PD-1) blockade monotherapy is effective in relapsed/refractory classical Hodgkin lymphoma (cHL), but a subset of patients is recalcitrant to PD-1 inhibitors and only a minority of patients achieves durable remission. Effective treatment regimens for those with relapsed/progressive cHL after single-agent anti-PD-1 are urgently needed. Anti-PD-1 combination with the DNA-demethylating agent decitabine showed positive preliminary results in our test cohort patients who were resistant to anti-PD-1. Here, we assess the efficacy of decitabine plus anti-PD-1 therapy in an expansion cohort and after longer follow-up. PATIENTS AND METHODS We present the response and progression-free survival rates from patients with relapsed/refractory cHL who relapsed/progressed after prior anti-PD-1 monotherapy, and who received decitabine (10 mg/day, days 1-5) plus the anti-PD-1 camrelizumab (200 mg, day 8), every 3 weeks in a phase II trial (ClinicalTrials.gov: NCT02961101 and NCT03250962). RESULTS Overall, 51 patients (test cohort: 25, expansion cohort: 26) were treated and 50 evaluated for efficacy. The objective response rate was 52% [nine complete responses (CR); 36%] in the test cohort, and 68% (six CRs; 24%) in the expansion cohort. Median progression-free survival with decitabine plus camrelizumab was 20.0 and 21.6 months, respectively, which was significantly longer than that achieved with prior anti-PD-1 monotherapy. Durable response was observed in an estimated 78% of patients who achieved CR at 24 months. After decitabine plus camrelizumab, the ratio increase of circulating peripheral central memory T cells directly correlated with both clinical response and progression-free survival. CONCLUSIONS Decitabine plus camrelizumab is associated with high response rates and long-term benefits in patients with relapsed/refractory cHL who failed PD-1 inhibitors.
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Affiliation(s)
- Chunmeng Wang
- Department of Bio-therapeutic, The First Medical Centre in Chinese PLA General Hospital, Beijing, P.R. China
| | - Yang Liu
- Department of Bio-therapeutic, The First Medical Centre in Chinese PLA General Hospital, Beijing, P.R. China
| | - Liang Dong
- Department of Bio-therapeutic, The First Medical Centre in Chinese PLA General Hospital, Beijing, P.R. China
| | - Xiang Li
- Department of Bio-therapeutic, The First Medical Centre in Chinese PLA General Hospital, Beijing, P.R. China
| | - Qingming Yang
- Department of Bio-therapeutic, The First Medical Centre in Chinese PLA General Hospital, Beijing, P.R. China
| | - Malcolm V Brock
- Department of Surgery, Johns Hopkins University, Baltimore, Maryland
| | - Qian Mei
- Department of Bio-therapeutic, The First Medical Centre in Chinese PLA General Hospital, Beijing, P.R. China
| | - Jiejie Liu
- Department of Bio-therapeutic, The First Medical Centre in Chinese PLA General Hospital, Beijing, P.R. China
| | - Meixia Chen
- Department of Bio-therapeutic, The First Medical Centre in Chinese PLA General Hospital, Beijing, P.R. China
| | - Fengxia Shi
- Department of Bio-therapeutic, The First Medical Centre in Chinese PLA General Hospital, Beijing, P.R. China
| | - Miao Liu
- Department of Statistics and Epidemiology, Graduate School of Chinese PLA General Hospital, Beijing, P.R. China
| | - Jing Nie
- Department of Bio-therapeutic, The First Medical Centre in Chinese PLA General Hospital, Beijing, P.R. China.
| | - Weidong Han
- Department of Bio-therapeutic, The First Medical Centre in Chinese PLA General Hospital, Beijing, P.R. China.
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13
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Cohen R, Rousseau B, Vidal J, Colle R, Diaz LA, André T. Immune Checkpoint Inhibition in Colorectal Cancer: Microsatellite Instability and Beyond. Target Oncol 2021; 15:11-24. [PMID: 31786718 DOI: 10.1007/s11523-019-00690-0] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Immune checkpoints inhibitors (ICIs) have been a breakthrough, with unique response and survival patterns compared with chemotherapy for patients with advanced Mismatch Repair-deficient/Microsatellite instable (dMMR/MSI) colorectal cancer, but have shown disappointing results in Mismatch Repair-proficient/Microsatellite stable (pMMR/MSS) colorectal cancer. As up to 50% of patients harboring dMMR/MSI advanced cancers will ultimately progress after PD-1 blockade, biomarkers are needed to predict response/resistance to immunotherapy and to select patients for immunomodulating combination therapies. Patients with pMMR/MSS colorectal cancer present with distinct immune profiles compared to dMMR/MSI tumors, giving evidence of different immune escape mechanisms, which could be overcome through individualized immunotherapeutic strategies. In this review we discuss the latest developments in the field of immunotherapy for dMMR/MSI and pMMR/MSS colorectal cancers, and unresolved questions and considerations concerning the use of ICI therapies in this population. Future immunomodulation strategies based on biomarker selection (tumor mutational burden, Immunoscore®, mutational profile) are discussed.
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Affiliation(s)
- Romain Cohen
- Sorbonne Université, Medical Oncology Department, Hôpital Saint-Antoine, AP-HP, 184 Rue du Faubourg Saint-Antoine, 75012, Paris, France.
| | - Benoît Rousseau
- Department of Medicine-Solid Tumor Division, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Joana Vidal
- Department of Medicine-Solid Tumor Division, Memorial Sloan Kettering Cancer Center, New York, USA
- Medical Oncology Department, Hospital del Mar-IMIM, CIBERONC Instituto de Salud Carlos III, Barcelona, Spain
| | - Raphaël Colle
- Sorbonne Université, Medical Oncology Department, Hôpital Saint-Antoine, AP-HP, 184 Rue du Faubourg Saint-Antoine, 75012, Paris, France
| | - Luis A Diaz
- Department of Medicine-Solid Tumor Division, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Thierry André
- Sorbonne Université, Medical Oncology Department, Hôpital Saint-Antoine, AP-HP, 184 Rue du Faubourg Saint-Antoine, 75012, Paris, France
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14
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Wei Y, Xiao X, Lao XM, Zheng L, Kuang DM. Immune landscape and therapeutic strategies: new insights into PD-L1 in tumors. Cell Mol Life Sci 2021; 78:867-887. [PMID: 32940722 PMCID: PMC11072479 DOI: 10.1007/s00018-020-03637-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 08/07/2020] [Accepted: 09/03/2020] [Indexed: 12/14/2022]
Abstract
PD-1/PD-L1 axis represents an important target for renormalizing and resetting anti-tumor immunity in cancer patients. Currently, anti-PD-1/PD-L1 therapy has been applied in a broad spectrum of tumors and has yielded durable remission in patients. However, how to further broaden the application, guide personalized therapeutic strategies, and improve clinical responses remains a vital task. At present, PD-L1 expression is an important parameter of clinical indications for immune checkpoint blockade in many types of cancers, a strategy based on the supposition that positive PD-L1 expression reflects local T cell response. Recent studies have revealed that PD-L1 expression is regulated by multiple layers of complicated factors, during which the host immune microenvironment exerts a pivotal role and determines the clinical efficacy of the therapy. In this review, we will summarize recent findings on PD-1/PD-L1 in cancer, focusing on how local immune landscape participates in the regulation of PD-L1 expression and modification. Importantly, we will also discuss these topics in the context of clinical treatment and analyze how these fundamental principles might inspire our efforts to develop more precise and effective immune therapeutics for cancer.
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Affiliation(s)
- Yuan Wei
- The Fifth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University, Guangzhou, China
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xiao Xiao
- Cancer Program, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Xiang-Ming Lao
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University, Guangzhou, China.
| | - Limin Zheng
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University, Guangzhou, China.
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University Cancer Center, Guangzhou, China.
| | - Dong-Ming Kuang
- The Fifth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University, Guangzhou, China.
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University Cancer Center, Guangzhou, China.
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15
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Barili V, Boni C, Rossi M, Vecchi A, Zecca A, Penna A, Missale G, Ferrari C, Fisicaro P. Metabolic regulation of the HBV-specific T cell function. Antiviral Res 2020; 185:104989. [PMID: 33248194 DOI: 10.1016/j.antiviral.2020.104989] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 11/16/2020] [Accepted: 11/19/2020] [Indexed: 12/15/2022]
Abstract
Chronically HBV infected subjects are more than 260 million worldwide; cirrhosis and liver cancer represent possible outcomes which affect around 700,000 patients per year. Both innate and adaptive immune responses are necessary for viral control and both have been shown to be defective in chronic patients. Metabolic remodeling is an essential process in T cell biology, particularly for T cell activation, differentiation and survival. Cellular metabolism relies on the conversion of nutrients into energy to support intracellular processes, and to generate fundamental intermediate components for cell proliferation and growth. Adaptive immune responses are the central mechanisms for the resolution of primary human infections leading to the activation of pathogen-specific B and T cell functions. In chronic HBV infection the anti-viral immune response fails to contain the virus and leads to persistent hepatic tissue damage which may finally result in liver cirrhosis and cancer. This T cell failure is associated with metabolic alterations suggesting that control of nutrient uptake and intracellular utilization as well as correct regulation of intracellular metabolic pathways are strategic for T cell differentiation during persistent chronic infections. This review will discuss some of the main features of the T cell metabolic processes which are relevant to the generation of an efficient antiviral response, with specific focus on their clinical relevance in chronic HBV infection in the perspective of possible strategies to correct deregulated metabolic pathways underlying T cell dysfunction of chronic HBV patients.
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Affiliation(s)
- Valeria Barili
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Carolina Boni
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Marzia Rossi
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Andrea Vecchi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Alessandra Zecca
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Amalia Penna
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Gabriele Missale
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Carlo Ferrari
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
| | - Paola Fisicaro
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
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16
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Hoyek S, Kourie HR, Labaki C, Antoun J. Immune checkpoint inhibitors in ocular melanomas: contrasting efficacy with cutaneous melanomas. Immunotherapy 2020; 12:1149-1152. [PMID: 33076742 DOI: 10.2217/imt-2020-0234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Sandra Hoyek
- Ophtalmology Department, Faculty of Medicine, Saint Joseph University of Beirut, Lebanon
| | - Hampig Raphael Kourie
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Lebanon
| | - Chris Labaki
- Faculty of Medicine, Saint Joseph University of Beirut, Lebanon
| | - Joelle Antoun
- Ophtalmology Department, Faculty of Medicine, Saint Joseph University of Beirut, Lebanon
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17
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Mamdani H, Jalal SI. Histone Deacetylase Inhibition in Non-small Cell Lung Cancer: Hype or Hope? Front Cell Dev Biol 2020; 8:582370. [PMID: 33163495 PMCID: PMC7581936 DOI: 10.3389/fcell.2020.582370] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 09/22/2020] [Indexed: 12/21/2022] Open
Abstract
Epigenetic modulation, including acetylation, methylation, phosphorylation, and ubiquitination, plays a pivotal role in regulation of gene expression. Histone acetylation-a balance between the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs)-is one of the key epigenetic events. Our understanding of the role of HDACs in cancer is evolving. A number of HDAC isoenzymes are overexpressed in a variety of malignancies. Aberrant histone acetylation is associated with dysregulation of tumor suppressor genes leading to development of several solid tumors and hematologic malignancies. Pre-clinical studies have demonstrated that HDAC-1 gene expression is associated with lung cancer progression. Histone hypoacetylation is associated with more aggressive phenotype in adenocarcinoma of the lung. HDAC inhibitors (HDACi) have pleiotropic cellular effects and induce the expression of pro-apoptotic genes/proteins, cause cellular differentiation and/or cell cycle arrest, inhibit angiogenesis, and inhibit transition to a mesenchymal phenotype. Consequently, treatment with HDACi has shown anti-proliferative activity in non-small cell lung cancer (NSCLC) cell lines. Despite promising results in pre-clinical studies, HDACi have shown only modest single agent activity in lung cancer clinical trials. HDAC activation has been implicated as one of the mechanisms causing resistance to chemotherapy, molecularly targeted therapy, and immune checkpoint inhibition. Therefore, there is a growing interest in combining HDACi with these agents to enhance their efficacy or reverse resistance. In this paper, we review the available preclinical and clinical evidence for the use of HDACi in NSCLC. We also review the challenges precluding widespread clinical utility of HDACi as a cancer therapy and future directions.
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Affiliation(s)
- Hirva Mamdani
- Department of Oncology, Karmanos Cancer Institute, Detroit, MI, United States
| | - Shadia I. Jalal
- Department of Internal Medicine, Division of Hematology/Oncology, Indiana University, Indianapolis, IN, United States
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18
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Salavatiha Z, Soleimani-Jelodar R, Jalilvand S. The role of endogenous retroviruses-K in human cancer. Rev Med Virol 2020; 30:1-13. [PMID: 32734655 DOI: 10.1002/rmv.2142] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 12/15/2022]
Abstract
It is known that human endogenous retroviruses (HERVs) constitute almost 8% of the human genome. Although the expression of HERVs from the human genome is tightly regulated, different exogenous and endogenous factors could trigger HERV activation. Aberrant expression of different HERVs may potentially cause a variety of diseases such as neurological and autoimmune diseases as well as cancer. It is suggested that HERV-K can induce cancer through different mechanisms that are discussed. The interplay between some tumor viruses and HERV-K seems to be a key player in progression of viral-associated cancers because elevated levels of Rec and Np9 proteins are observed in several cancers. The frequent over expression of HERV proteins and some specific antibodies in cancer cells could be considered as suitable prognostic and therapeutic biomarkers in diagnosis and treatment of cancers. The expression of HERV proteins in cancers and development of immune responses against them may also be used as targets for cancer immunotherapy. Further studies are warranted to evaluate the role of HERVs in cancer formation and use of different HERV proteins in developing new diagnostic and therapeutic approaches for cancer treatments.
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Affiliation(s)
- Zahra Salavatiha
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Rahim Soleimani-Jelodar
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Jalilvand
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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19
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McGoverne I, Dunn J, Batham J, Tu WJ, Chrisp J, Rao S. Epitherapy and immune checkpoint blockade: using epigenetic reinvigoration of exhausted and dysfunctional T cells to reimburse immunotherapy response. BMC Immunol 2020; 21:22. [PMID: 32316916 PMCID: PMC7175524 DOI: 10.1186/s12865-020-00353-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 04/07/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Cancer cells subvert natural immunosuppression by upregulating the expression of checkpoint proteins and their ligands. For example, tumor cells expressing programmed death-ligand 1 (PD-L1) induce immune cell tolerance to cancers, thereby facilitating tumor progression. The recent clinical success of immunotherapy, particularly checkpoint blockade, represents a significant advance in cancer therapy. However, many cancers develop resistance to immunotherapies, and the underlying mechanisms and how these might be exploited to overcome resistance still need to be determined. METHODS T cell dysfunction, in part caused by chronic T cell receptor stimulation, diminishes the capacity for durable responses to checkpoint blockade. Furthermore, T cell populations are phenotypically and functionally heterogeneous, resulting in varying responses to checkpoint blockade. Recent molecular studies of T cell heterogeneity have shown that checkpoint blockade on its own does not alter the epigenetic landscape of T cells, despite epigenetic changes governing T cell phenotype. CONCLUSION Here we argue that epigenetic modifiers can be used to prime and sensitize T cells to immunotherapy. Administering epitherapy in conjunction with checkpoint blockade could decrease T cell exhaustion and immunotherapy resistance in many cancer types.
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Affiliation(s)
- Isabella McGoverne
- Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, Australia
| | - Jenny Dunn
- Gene Regulation and Translational Medicine Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Jacob Batham
- Melanie Swan Memorial Translational Centre, Faculty of Science and Technology, University of Canberra, Canberra, Australia
| | - Wen Juan Tu
- Gene Regulation and Translational Medicine Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | | | - Sudha Rao
- Gene Regulation and Translational Medicine Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
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20
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Kaštelan S, Antunica AG, Oresković LB, Pelčić G, Kasun E, Hat K. Immunotherapy for Uveal Melanoma - Current Knowledge and Perspectives. Curr Med Chem 2020; 27:1350-1366. [DOI: 10.2174/0929867326666190704141444] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 06/09/2019] [Accepted: 06/14/2019] [Indexed: 12/17/2022]
Abstract
Uveal melanoma is the most prevalent primary intraocular tumour in adults with
the incidence between five and six cases per million people in the United States and Europe.
The prognosis of patients with uveal melanoma is unfavourable with a 5-year survival rate of
50-70% despite significant advances in local tumour treatment using radiotherapy or surgical
resection. Approximately 50% of the patients develop metastases within 15 years from initial
diagnosis, mostly in the liver. The median survival rate after the onset of metastases is 6
months. Potential treatment options for metastatic uveal melanoma are chemotherapy, targeted
therapy, and immunotherapy but no method showed satisfactory results. Immunotherapy
with checkpoint inhibition showed promising results in the treatment of cutaneous melanoma;
however, it did not appear to be equally effective with uveal melanoma. This may be
due to differences in mutational burden, expression of neoantigens between these two types of
tumour, immunosuppressive tumour microenvironment, and low immunogenicity and immune
privilege of uveal melanoma. Considering the disappointing results of treatment with
anti-CTLA-4 and PD-1/PD-L1 blockade in patients with advanced uveal melanoma several
new forms of therapies are being developed. This may include immunotherapy with
IMCgp100, glembatumumab vedotin and the infusion of autologous TILs, targeted therapy
with selective MEK inhibitors, epigenetic therapy, and nanotherapy. Better insight into the
molecular and genetic profile of uveal melanoma will facilitate detection of new prognostic
biomarkers and thus enable a better modification of the existing immunotherapy methods and
development of new forms of treatment specifically designed for uveal melanoma patients.
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Affiliation(s)
- Snježana Kaštelan
- Department of Ophthalmology, University Hospital Dubrava, Zagreb, Croatia
| | | | | | - Goran Pelčić
- Department of Ophthalmology, Faculty of Medicine, University of Rijeka and Clinical Hospital Center Rijeka, Rijeka, Croatia
| | - Ema Kasun
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Koraljka Hat
- Department of Maxillofacial Surgery, University Hospital Dubrava, Zagreb, Croatia
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21
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Xiao G, Jin LL, Liu CQ, Wang YC, Meng YM, Zhou ZG, Chen J, Yu XJ, Zhang YJ, Xu J, Zheng L. EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma. J Immunother Cancer 2019; 7:300. [PMID: 31727135 PMCID: PMC6854886 DOI: 10.1186/s40425-019-0784-9] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 10/22/2019] [Indexed: 12/13/2022] Open
Abstract
Background Accumulating studies suggest that targeting epigenetic modifications could improve the efficacy of tumor immunotherapy; however, the mechanisms underlying this phenomenon remain largely unknown. Here, we investigated the ability of the epigenetic modifier, enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), to regulate the expression of immune checkpoint inhibitor, programmed death-1 ligand 1 (PD-L1) in hepatocellular carcinoma (HCC). Methods Immunohistochemistry and multiplex immunofluorescence staining were performed to analyze the expression and correlation of EZH2 and PD-L1 in HCC tissues. Immunoblotting, quantitative real-time PCR, flow cytometry, chromatin immunoprecipitation, and dual-luciferase reporter gene assays were performed to evaluate the regulatory roles of EZH2 on PD-L1 expression. Results In vitro cell experiments revealed that EZH2 negatively regulated the PD-L1 expression of hepatoma cell lines in IFNγ-dependent manner. Mechanistic studies demonstrated that EZH2 could suppress PD-L1 expression by upregulating the H3K27me3 levels on the promoters of CD274 (encoding PD-L1) and interferon regulatory factor 1 (IRF1), an essential transcription factor for PD-L1 expression, without affecting the activation of the IFNγ-signal transducer and activator of transcription 1 (STAT1) pathway. Clinical samples from HCC patients with immune-activated microenvironments showed negative correlations between EZH2 and PD-L1 expression in hepatoma cells. Multivariate Cox analysis demonstrated that the combination of EZH2 and PD-L1 was an independent prognostic factor for both OS and RFS for patients with HCC. Conclusions The epigenetic modificator EZH2 can suppress the expression of immune checkpoint inhibitor PD-L1 by directly upregulating the promoter H3K27me3 levels of CD274 and IRF1 in hepatoma cells, and might serve as a potential therapeutic target for combination of immunotherapy for immune-activated HCC.
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Affiliation(s)
- Gang Xiao
- Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.,Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Li-Lian Jin
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, People's Republic of China
| | - Chao-Qun Liu
- Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.,Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Yong-Chun Wang
- Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Ya-Ming Meng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, People's Republic of China
| | - Zhong-Guo Zhou
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Jing Chen
- Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Xing-Juan Yu
- Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Yao-Jun Zhang
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Jing Xu
- Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.
| | - Limin Zheng
- Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China. .,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
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22
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Kim DH, Kim HM, Huong PTT, Han HJ, Hwang J, Cha-Molstad H, Lee KH, Ryoo IJ, Kim KE, Huh YH, Ahn JS, Kwon YT, Soung NK, Kim BY. Enhanced anticancer effects of a methylation inhibitor by inhibiting a novel DNMT1 target, CEP 131, in cervical cancer. BMB Rep 2019. [PMID: 31068247 PMCID: PMC6549914 DOI: 10.5483/bmbrep.2019.52.5.055] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Methylation is a primary epigenetic mechanism regulating gene expression. 5-aza-2′-deoxycytidine is an FDA-approved drug prescribed for treatment of cancer by inhibiting DNA-Methyl-Transferase 1 (DNMT1). Results of this study suggest that prolonged treatment with 5-aza-2′-deoxycytidine could induce centrosome abnormalities in cancer cells and that CEP131, a centrosome protein, is regulated by DNMT1. Interestingly, cancer cell growth was attenuated in vitro and in vivo by inhibiting the expression of Cep131. Finally, Cep131-deficient cells were more sensitive to treatment with DNMT1 inhibitors. These findings suggest that Cep131 is a potential novel anti-cancer target. Agents that can inhibit this protein may be useful alone or in combination with DNMT1 inhibitors to treat cancer.
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Affiliation(s)
- Dong Hyun Kim
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116; Department of Bio-Molecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Korea
| | - Hye-Min Kim
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116, Korea
| | - Pham Thi Thu Huong
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116, Korea
| | - Ho-Jin Han
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116; Department of Bio-Molecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Korea
| | - Joonsung Hwang
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116, Korea
| | - Hyunjoo Cha-Molstad
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116, Korea
| | - Kyung Ho Lee
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116, Korea
| | - In-Ja Ryoo
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116, Korea
| | - Kyoon Eon Kim
- Department of Biochemistry, College of Natural Science, Chungnam National University, Daejeon 34134, Korea
| | - Yang Hoon Huh
- Center for Electron Microscopy Research, Korea Basic Science Institute, Cheongju 28119, Korea
| | - Jong Seog Ahn
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116; Department of Bio-Molecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Korea
| | - Yong Tae Kwon
- Protein Metabolism Medical Research Center, Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea
| | - Nak-Kyun Soung
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116; Department of Bio-Molecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Korea
| | - Bo Yeon Kim
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116; Department of Bio-Molecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Korea
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23
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Gray JE, Saltos A, Tanvetyanon T, Haura EB, Creelan B, Antonia SJ, Shafique M, Zheng H, Dai W, Saller JJ, Chen Z, Tchekmedyian N, Goas K, Thapa R, Boyle TA, Chen DT, Beg AA. Phase I/Ib Study of Pembrolizumab Plus Vorinostat in Advanced/Metastatic Non-Small Cell Lung Cancer. Clin Cancer Res 2019; 25:6623-6632. [PMID: 31409616 DOI: 10.1158/1078-0432.ccr-19-1305] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 06/20/2019] [Accepted: 08/06/2019] [Indexed: 12/26/2022]
Abstract
PURPOSE Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase I/Ib trial, we tested the oral HDACi vorinostat combined with the programmed cell death protein 1 inhibitor pembrolizumab in advanced/metastatic non-small cell lung cancer. PATIENTS AND METHODS Patients received intravenous pembrolizumab (200 mg every 3 weeks) plus oral vorinostat (200 or 400 mg/day). Primary endpoint was safety/tolerability. Secondary endpoints included response rate, progression-free survival, disease control rate (DCR), and overall survival. Tumor gene expression changes, T-cell density, and myeloid cell levels were studied in serial tissue specimens. RESULTS Thirty-three patients were treated (13 in phase I, 20 in phase Ib). In phase I, both ICI-naïve and ICI-pretreated patients were enrolled to determine dose-limiting toxicities (DLT). No DLTs were observed, and the recommended phase I dose was pembrolizumab 200 mg and vorinostat 400 mg. Any-grade adverse events were mainly fatigue (33%) and nausea/vomiting (27%). Of six ICI-naïve and 24 ICI-pretreated patients evaluable for response, four (13%) had partial response [two confirmed, one unconfirmed with subsequent prolonged stable disease (SD), one unconfirmed with subsequent progressive disease (PD)], 16 (53%) had SD, and 10 (33%) had PD for a DCR of 67%. In the ICI-pretreated cohort, three patients (one confirmed, two unconfirmed) had partial response and 10 had SD. Pretreatment CD8+ T-cell presence in tumor stromal regions was associated with treatment benefit. CONCLUSIONS Pembrolizumab plus vorinostat was well tolerated and demonstrated preliminary antitumor activity despite progression on prior ICI treatment.
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Affiliation(s)
- Jhanelle E Gray
- Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
| | - Andreas Saltos
- Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Tawee Tanvetyanon
- Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Eric B Haura
- Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Ben Creelan
- Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Scott J Antonia
- Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Michael Shafique
- Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Hong Zheng
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Wenjie Dai
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - James J Saller
- Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.,Department of Anatomic Pathology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Zhihua Chen
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | | | - Kristen Goas
- Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Ram Thapa
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Theresa A Boyle
- Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.,Department of Anatomic Pathology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Dung-Tsa Chen
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Amer A Beg
- Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida. .,Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, Florida
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24
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Jespersen H, Olofsson Bagge R, Ullenhag G, Carneiro A, Helgadottir H, Ljuslinder I, Levin M, All-Eriksson C, Andersson B, Stierner U, Nilsson LM, Nilsson JA, Ny L. Concomitant use of pembrolizumab and entinostat in adult patients with metastatic uveal melanoma (PEMDAC study): protocol for a multicenter phase II open label study. BMC Cancer 2019; 19:415. [PMID: 31046743 PMCID: PMC6498539 DOI: 10.1186/s12885-019-5623-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 04/18/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND While recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in metastatic uveal melanoma. Thus, metastatic uveal melanoma remains a disease with an urgent unmet medical need. Reports of treatment with immune checkpoint inhibitors have thus far been disappointing. Based on animal experiments, it is reasonable to hypothesize that the effect of immunotherapy may be augmented by epigenetic therapy. Proposed mechanisms include enhanced expression of HLA class I and cancer antigens on cancer cells, as well as suppression of myeloid suppressor cells. METHODS The PEMDAC study is a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD1 inhibitor pembrolizumab and the class I HDAC inhibitor entinostat in adult patients with metastatic uveal melanoma. Primary endpoint is objective response rate. Eligible patients have histologically confirmed metastatic uveal melanoma, ECOG performance status 0-1, measurable disease as per RECIST 1.1 and may have received any number of prior therapies, with the exception of anticancer immunotherapy. Twenty nine patients will be enrolled. Patients receive pembrolizumab 200 mg intravenously every third week in combination with entinostat 5 mg orally once weekly. Treatment will continue until progression of disease or intolerable toxicity or for a maximum of 24 months. DISCUSSION The PEMDAC study is the first trial to assess whether the addition of an HDAC inhibitor to anti-PD1 therapy can yield objective anti-tumoral responses in metastatic UM. TRIAL REGISTRATION ClinicalTrials.gov registration number: NCT02697630 . (Registered 3 March 2016). EudraCT registration number: 2016-002114-50.
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Affiliation(s)
- Henrik Jespersen
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Blå stråket 2, 413 45, Gothenburg, Sweden
| | - Roger Olofsson Bagge
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Blå stråket 5, 413 45, Gothenburg, Sweden
| | - Gustav Ullenhag
- Department of Radiology, Oncology and Radiation Science, Section of Oncology, Uppsala University, 751 05, Uppsala, Sweden
| | - Ana Carneiro
- Department of Oncology, Skåne University Hospital, Getingevägen 4, 221 85, Lund, Sweden
| | - Hildur Helgadottir
- Department of Oncology, Karolinska University Hospital, Karolinska vägen, 171 76, Stockholm, Sweden
| | - Ingrid Ljuslinder
- Department of Oncology, Norrlands University Hospital, 901 85, Umeå, Sweden
| | - Max Levin
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Blå stråket 2, 413 45, Gothenburg, Sweden
| | | | - Bengt Andersson
- Department of Clinical immunology and transfusion medicine, Sahlgrenska University Hospital, Guldhedsgatan 10, 413 45, Gothenburg, Sweden
| | - Ulrika Stierner
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Blå stråket 2, 413 45, Gothenburg, Sweden
| | - Lisa M Nilsson
- Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Medicinaregatan 1F, 405 30, Gothenburg, Sweden
| | - Jonas A Nilsson
- Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Medicinaregatan 1F, 405 30, Gothenburg, Sweden
| | - Lars Ny
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Blå stråket 2, 413 45, Gothenburg, Sweden.
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25
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van den Bulk J, Verdegaal EM, de Miranda NF. Cancer immunotherapy: broadening the scope of targetable tumours. Open Biol 2019; 8:rsob.180037. [PMID: 29875199 PMCID: PMC6030119 DOI: 10.1098/rsob.180037] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 05/11/2018] [Indexed: 12/12/2022] Open
Abstract
Cancer immunotherapy has experienced remarkable advances in recent years. Striking clinical responses have been achieved for several types of solid cancers (e.g. melanoma, non-small cell lung cancer, bladder cancer and mismatch repair-deficient cancers) after treatment of patients with T-cell checkpoint blockade therapies. These have been shown to be particularly effective in the treatment of cancers with high mutation burden, which places tumour-mutated antigens (neo-antigens) centre stage as targets of tumour immunity and cancer immunotherapy. With current technologies, neo-antigens can be identified in a short period of time, which may support the development of complementary, personalized approaches that increase the number of tumours amenable to immunotherapeutic intervention. In addition to reviewing the state of the art in cancer immunotherapy, we discuss potential avenues that can bring the immunotherapy revolution to a broader patient group including cancers with low mutation burden.
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26
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Morra F, Merolla F, Criscuolo D, Insabato L, Giannella R, Ilardi G, Cerrato A, Visconti R, Staibano S, Celetti A. CCDC6 and USP7 expression levels suggest novel treatment options in high-grade urothelial bladder cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:90. [PMID: 30786932 PMCID: PMC6381716 DOI: 10.1186/s13046-019-1087-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 02/06/2019] [Indexed: 12/29/2022]
Abstract
Background The muscle invasive form of urothelial bladder cancer (UBC) is a deadly disease. Currently, the therapeutic approach of UBC is mostly based on surgery and standard chemotherapy. Biomarkers to establish appropriate drugs usage are missing. Deficiency of the tumor suppressor CCDC6 determines PARP-inhibitor sensitivity. The CCDC6 levels are modulated by the deubiquitinase USP7. In this work we scored CCDC6 and USP7 expression levels in primary UBC and we evaluated the expression levels of CCDC6 in correlation with the effects of the PARP-inhibitors combined with the USP7 inhibitor, P5091, in vitro. Since PARP-inhibitors could be enhanced by conventional chemotherapy or DNA damage inducers, we tested the new agent RRx-001, able to induce DNA damage, to prove the benefit of combined treatments in bladder cancer cells. Methods The J82, T24, 5637 and KU-19-19 bladder cancer cells were exposed to USP7 inhibitor P5091 in presence of cycloheximide to analyse the CCDC6 stability. Upon the CCDC6 degradation induced by P5091, the cells sensitivity to PARP-inhibitor was evaluated by cell viability assays. The ability of the DNA damage inducer RRx-001 to modulate CCDC6 protein levels and H2AX phosphorylation was detected at immunoblot. The combination of USP7 inhibitor plus RRx-001 enhanced the PARP-inhibitor sensitivity, as evaluated by cell viability assays. The results of the scores and correlation of CCDC6 and USP7 expression levels obtained by UBC primary biopsies staining were used to cluster patients by a K-mean cluster analysis. Results P5091 determining CCDC6 degradation promoted bladder cancer cells sensitivity to PARP-inhibitor drugs. RRx-001, by inducing DNA damage, enhanced the effects of the combined treatment. The immunohistochemical staining of both CCDC6 and USP7 proteins allowed to cluster the high grade (G3) UBC patients, on the basis of CCDC6 expression levels. Conclusions In high grade UBC the identification of two clusters of patients based on CCDC6 and USP7 expession can possibly indicate the use of PARP-inhibitor drugs, in combination with USP7 inhibitor in addition to the DNA damage inducer RRx-001, that also acts as an immunomodulatory agent, offering novel therapeutic strategy for personalized medicine in bladder cancer patients. Electronic supplementary material The online version of this article (10.1186/s13046-019-1087-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Francesco Morra
- Institute for the Experimental Endocrinology and Oncology, Research National Council, CNR, Naples, Italy
| | - Francesco Merolla
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Daniela Criscuolo
- Institute for the Experimental Endocrinology and Oncology, Research National Council, CNR, Naples, Italy
| | - Luigi Insabato
- Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy
| | | | - Gennaro Ilardi
- Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy
| | - Aniello Cerrato
- Institute for the Experimental Endocrinology and Oncology, Research National Council, CNR, Naples, Italy
| | - Roberta Visconti
- Institute for the Experimental Endocrinology and Oncology, Research National Council, CNR, Naples, Italy
| | - Stefania Staibano
- Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy
| | - Angela Celetti
- Institute for the Experimental Endocrinology and Oncology, Research National Council, CNR, Naples, Italy.
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27
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Bacolod MD, Barany F, Pilones K, Fisher PB, de Castro RJ. Pathways- and epigenetic-based assessment of relative immune infiltration in various types of solid tumors. Adv Cancer Res 2019; 142:107-143. [PMID: 30885360 DOI: 10.1016/bs.acr.2019.01.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Recent clinical studies document the power of immunotherapy in treating subsets of patients with advanced cancers. In this context and with multiple cancer immunotherapeutics already evaluated in the clinic and a large number in various stages of clinical trials, it is imperative to comprehensively examine genomics data to better comprehend the role of immunity in different cancers in predicting response to therapy and in directing appropriate therapies. The approach we chose is to scrutinize the pathways and epigenetic factors predicted to drive immune infiltration in different cancer types using publicly available TCGA transcriptional and methylation datasets, along with accompanying clinico-pathological data. We observed that the relative activation of T cells and other immune signaling pathways differs across cancer types. For example, pathways related to activation and proliferation of helper and cytotoxic T cells appear to be more highly enriched in kidney, skin, head and neck, and esophageal cancers compared to those of lung, colorectal, and liver or bile duct cancers. The activation of these immune-related pathways positively associated with prognosis in certain cancer types, most notably melanoma, head and neck, and cervical cancers. Integrated methylation and expression data (along with publicly available, ENCODE-generated histone ChIP Seq and DNAse hypersensitivity data) predict that epigenetic regulation is a primary factor driving transcriptional activation of a number of genes crucial to immunity in cancer, including T cell receptor genes (e.g., CD3D, CD3E), CTLA4, and GZMA. However, the extent to which epigenetic factors (primarily methylation at promoter regions) affect transcription of immune-related genes may vary across cancer types. For example, there is a high negative correlation between promoter CpG methylation and CD3D expression in renal and thyroid cancers, but not in brain tumors. The types of analyses we have undertaken provide insights into the relationships between immune modulation and cancer etiology and progression, offering clues into ways of therapeutically manipulating the immune system to promote immune recognition and immunotherapy.
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Affiliation(s)
- Manny D Bacolod
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, United States.
| | - Francis Barany
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, United States
| | - Karsten Pilones
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
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Prasanna T, Wu F, Khanna KK, Yip D, Malik L, Dahlstrom JE, Rao S. Optimizing poly (ADP-ribose) polymerase inhibition through combined epigenetic and immunotherapy. Cancer Sci 2018; 109:3383-3392. [PMID: 30230653 PMCID: PMC6215877 DOI: 10.1111/cas.13799] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 09/05/2018] [Accepted: 09/09/2018] [Indexed: 12/31/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in targeted and immune-directed therapies for other solid organ malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective anticancer drugs that produce good initial clinical responses, especially in homologous recombination DNA repair-deficient cancers. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival. Many efforts have been made to overcome PARPi resistance, mostly by targeting genes and effector proteins participating in homologous recombination that are overexpressed during PARPi therapy. Due to many known and unknown compensatory pathways, genes, and effector proteins, overlap and shared resistance are common. Overexpression of programmed cell death-ligand 1 (PD-L1) and cancer stem cell (CSC) sparing are novel PARPi resistance hypotheses. Although adding programmed cell death-1 (PD-1)/PD-L1 inhibitors to PARPi might improve immunogenic cell death and be crucial for durable responses, they are less likely to target the CSC population that drives recurrent tumor growth. Lysine-specific histone demethylase-1A and histone deacetylase inhibitors have shown promising activity against CSCs. Combining epigenetic drugs such as lysine-specific histone demethylase-1A inhibitors or histone deacetylase inhibitors with PARPi/anti-PD-1/PD-L1 is a novel, potentially synergistic strategy for priming tumors and overcoming resistance. Furthermore, such an approach could pave the way for the identification of new upstream epigenetic and genetic signatures.
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Affiliation(s)
- Thiru Prasanna
- Health Research InstituteFaculty of ESTeMUniversity of CanberraCanberraACTAustralia
- Department of Medical OncologyThe Canberra HospitalCanberraACTAustralia
| | - Fan Wu
- Health Research InstituteFaculty of ESTeMUniversity of CanberraCanberraACTAustralia
| | - Kum Kum Khanna
- QIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia
| | - Desmond Yip
- Department of Medical OncologyThe Canberra HospitalCanberraACTAustralia
- ANU Medical SchoolAustralian National UniversityCanberraACTAustralia
| | - Laeeq Malik
- Department of Medical OncologyThe Canberra HospitalCanberraACTAustralia
- ANU Medical SchoolAustralian National UniversityCanberraACTAustralia
| | - Jane E. Dahlstrom
- ANU Medical SchoolAustralian National UniversityCanberraACTAustralia
- Department of Anatomical PathologyACT PathologyThe Canberra HospitalCanberraACTAustralia
| | - Sudha Rao
- Health Research InstituteFaculty of ESTeMUniversity of CanberraCanberraACTAustralia
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Marshall HT, Djamgoz MBA. Immuno-Oncology: Emerging Targets and Combination Therapies. Front Oncol 2018; 8:315. [PMID: 30191140 PMCID: PMC6115503 DOI: 10.3389/fonc.2018.00315] [Citation(s) in RCA: 234] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 07/24/2018] [Indexed: 12/20/2022] Open
Abstract
Host immunity recognizes and eliminates most early tumor cells, yet immunological checkpoints, exemplified by CTLA-4, PD-1, and PD-L1, pose a significant obstacle to effective antitumor immune responses. T-lymphocyte co-inhibitory pathways influence intensity, inflammation and duration of antitumor immunity. However, tumors and their immunosuppressive microenvironments exploit them to evade immune destruction. Recent PD-1 checkpoint inhibitors yielded unprecedented efficacies and durable responses across advanced-stage melanoma, showcasing potential to replace conventional radiotherapy regimens. Neverthless, many clinical problems remain in terms of efficacy, patient-to-patient variability, and undesirable outcomes and side effects. In this review, we evaluate recent advances in the immuno-oncology field and discuss ways forward. First, we give an overview of current immunotherapy modalities, involving mainy single agents, including inhibitor monoclonal antibodies (mAbs) targeting T-cell checkpoints of PD-1 and CTLA-4. However, neoantigen recognition alone cannot eliminate tumors effectively in vivo given their inherent complex micro-environment, heterogeneous nature and stemness. Then, based mainly upon CTLA-4 and PD-1 checkpoint inhibitors as a "backbone," we cover a range of emerging ("second-generation") therapies incorporating other immunotherapies or non-immune based strategies in synergistic combination. These include targeted therapies such as tyrosine kinase inhibitors, co-stimulatory mAbs, bifunctional agents, epigenetic modulators (such as inhibitors of histone deacetylases or DNA methyltransferase), vaccines, adoptive-T-cell therapy, nanoparticles, oncolytic viruses, and even synthetic "gene circuits." A number of novel immunotherapy co-targets in pre-clinical development are also introduced. The latter include metabolic components, exosomes and ion channels. We discuss in some detail of the personalization of immunotherapy essential for ultimate maximization of clinical outcomes. Finally, we outline possible future technical and conceptual developments including realistic in vitro and in vivo models and inputs from physics, engineering, and artificial intelligence. We conclude that the breadth and quality of immunotherapeutic approaches and the types of cancers that can be treated will increase significantly in the foreseeable future.
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Affiliation(s)
- Henry T Marshall
- Neuroscience Solutions to Cancer Research Group, Department of Life Sciences, Imperial College London, London, United Kingdom
| | - Mustafa B A Djamgoz
- Neuroscience Solutions to Cancer Research Group, Department of Life Sciences, Imperial College London, London, United Kingdom
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Ma Y, Shen J, Wang LX. Successful treatment of high-risk myelodysplastic syndrome with decitabine-based chemotherapy followed by haploidentical lymphocyte infusion: A case report and literature review. Medicine (Baltimore) 2018; 97:e0434. [PMID: 29668607 PMCID: PMC5916686 DOI: 10.1097/md.0000000000010434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
RATIONALE The current therapy for elderly patients with high-risk myelodysplastic syndromes (MDSs) remains unsatisfactory. Decitabine, which has been approved to treat MDS, cannot eliminate malignant clones of MDS. PATIENT CONCERNS A 68-year-old woman presented with multiple divergent bleeding points in the subcutaneous tissue of the limb. Two years earlier, she had been diagnosed with invasive ductal carcinoma of the left breast and had undergone left modified radical mastectomy and local radiation therapy. DIAGNOSES The patient was diagnosed with MDS refractory anemia with excess of blast II and was classified as very high risk according to the revised international prognostic scoring system. INTERVENTIONS The chemotherapy regimen consisted of decitabine (20 mg/m intravenously on days 1-5), cytarabine (10 mg/m every 12 hours subcutaneously on days 1-5), aclarubicin hydrochloride (20 mg intravenously on days 1, 3, and 5), and recombinant human granulocyte colony-stimulating factor (250 μg/d subcutaneously from day 0 to day 5). Peripheral mononuclear cells from her son were infused at 36 hours after the end of each chemotherapy cycle. The patient received a total of 4 cycles of the therapy. OUTCOMES The patient achieved complete remission after the first cycle of the treatment. There was no clinical evidence of MDS relapse as of 4 years after the completion of the treatment. LESSONS The results suggested that decitabine-based chemotherapy and haploidentical lymphocyte infusion may be act synergistically. Combination therapy is a suitable, safe, and effective treatment regimen for elderly patients with high-risk MDS.
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Boulding T, McCuaig RD, Tan A, Hardy K, Wu F, Dunn J, Kalimutho M, Sutton CR, Forwood JK, Bert AG, Goodall GJ, Malik L, Yip D, Dahlstrom JE, Zafar A, Khanna KK, Rao S. LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer. Sci Rep 2018; 8:73. [PMID: 29311580 PMCID: PMC5758711 DOI: 10.1038/s41598-017-17913-x] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 12/04/2017] [Indexed: 12/23/2022] Open
Abstract
Complex regulatory networks control epithelial-to-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs. LSD1 phosphorylation at serine-111 (LSD1-s111p) by chromatin anchored protein kinase C-theta (PKC-θ), is critical for its demethylase and EMT promoting activity and LSD1-s111p is enriched in chemoresistant cells in vivo. LSD1 couples to PKC-θ on the mesenchymal gene epigenetic template promotes LSD1-mediated gene induction. In vivo, chemotherapy reduced tumour volume, and when combined with an LSD1 inhibitor, abrogated the mesenchymal signature and promoted an innate, M1 macrophage-like tumouricidal immune response. Circulating tumour cells (CTCs) from metastatic breast cancer (MBC) patients were enriched with LSD1 and pharmacological blockade of LSD1 suppressed the mesenchymal and stem-like signature in these patient-derived CTCs. Overall, LSD1 inhibition may serve as a promising epigenetic adjuvant therapy to subvert its pleiotropic roles in breast cancer progression and treatment resistance.
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Affiliation(s)
- T Boulding
- Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia
| | - R D McCuaig
- Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia
| | - A Tan
- Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia
| | - K Hardy
- Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia
| | - F Wu
- Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia
| | - J Dunn
- Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia
| | - M Kalimutho
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia
| | - C R Sutton
- Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia
| | - J K Forwood
- School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia
| | - A G Bert
- Gene Regulation Section, Centre for Cancer Biology, SA Pathology, Adelaide, SA, 5000, Australia
| | - G J Goodall
- Gene Regulation Section, Centre for Cancer Biology, SA Pathology, Adelaide, SA, 5000, Australia
| | - L Malik
- Department of Medical Oncology, The Canberra Hospital, Garran, ACT, 2605, Australia
- ANU Medical School, Australian National University, Acton, ACT, 2601, Australia
| | - D Yip
- Department of Medical Oncology, The Canberra Hospital, Garran, ACT, 2605, Australia
- ANU Medical School, Australian National University, Acton, ACT, 2601, Australia
| | - J E Dahlstrom
- Department of Anatomical Pathology, ACT Pathology, The Canberra Hospital, Garran, ACT, 2605, Australia
| | - A Zafar
- Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia
| | - K K Khanna
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia
| | - S Rao
- Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia.
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Cohen R, Svrcek M, Duval A, Parc Y, Österlund PP, André T. Immune checkpoint inhibitors for patients with colorectal cancer: mismatch repair deficiency and perspectives. COLORECTAL CANCER 2017. [DOI: 10.2217/crc-2017-0004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Harnessing the immune system to fight tumor cells is becoming a promising and innovative therapeutic strategy for a large spectrum of malignancies. The evaluation of immunotherapy in the context of colorectal cancers (CRCs) has brought to light mismatch repair deficiency as a major predictive biomarker for the efficacy of immune checkpoint blockade. In this review, we summarize the promising results of immune checkpoint inhibitors for patients with metastatic CRCs harboring mismatch repair deficiency, with special emphasis on further clinical development. Given the biological determinants of sensitivity to immune checkpoint blockade, we will also elucidate points that could unlock the potential of immunotherapy for patients with mismatch repair-proficient CRC.
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Affiliation(s)
- Romain Cohen
- Department of Medical Oncology, Hôpital Saint-Antoine, APHP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
- INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
- Sorbonne Universités, UPMC Univ., Paris 06, France
| | - Magali Svrcek
- INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
- Sorbonne Universités, UPMC Univ., Paris 06, France
- Department of Pathology, Hôpital Saint-Antoine, APHP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
| | - Alex Duval
- INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
| | - Yann Parc
- INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
- Sorbonne Universités, UPMC Univ., Paris 06, France
- Department of Digestive Surgery, Hôpital Saint-Antoine, APHP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
| | - Pia P Österlund
- Department of Oncology, Tampere University Hospital, Teiskontie 35, 33520 Tampere, Finland
| | - Thierry André
- Department of Medical Oncology, Hôpital Saint-Antoine, APHP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
- INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
- Sorbonne Universités, UPMC Univ., Paris 06, France
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张 少, 薛 志. [Progress of Epigenetic Methylation in Lung Cancer Research]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2017; 20:635-640. [PMID: 28935018 PMCID: PMC5973367 DOI: 10.3779/j.issn.1009-3419.2017.09.08] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/20/2017] [Accepted: 05/12/2017] [Indexed: 11/28/2022]
Abstract
Lung cancer is becoming an increasing threat to Chinese residents and its incidence continues to rise while the treatment effect is far from satisfactory. Hence, it is essential to improve the level of early diagnosis, treatment, prognosis in lung cancer. An epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence. The epigenetic studies, such as DNA methylation and histone methylation, are progressing rapidly in oncology research. A comprehensive understanding of its development status and existing problems is of great significance for the future research and the implementation of precision medicine. Herein, we aim to outline the progress of DNA methylation and histone methylation modification in lung cancer and make a prospect for the future research.
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Affiliation(s)
- 少伟 张
- />100853 北京,中国人民解放军总医院胸外科一病区Department of Toracic Surgery, PLA General Hospital, Beijing 100853, China
| | - 志强 薛
- />100853 北京,中国人民解放军总医院胸外科一病区Department of Toracic Surgery, PLA General Hospital, Beijing 100853, China
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Dunn J, Rao S. Epigenetics and immunotherapy: The current state of play. Mol Immunol 2017; 87:227-239. [PMID: 28511092 DOI: 10.1016/j.molimm.2017.04.012] [Citation(s) in RCA: 151] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Revised: 04/14/2017] [Accepted: 04/22/2017] [Indexed: 12/14/2022]
Abstract
Cancer cells employ a number of mechanisms to escape immunosurveillance and facilitate tumour progression. The recent explosion of interest in immunotherapy, especially immune checkpoint blockade, is a result of discoveries about the fundamental ligand-receptor interactions that occur between immune and cancer cells within the tumour microenvironment. Distinct ligands expressed by cancer cells engage with cell surface receptors on immune cells, triggering inhibitory pathways (such as PD-1/PD-L1) that render immune cells immunologically tolerant. Importantly, recent studies on the role of epigenetics in immune evasion have exposed a key role for epigenetic modulators in augmenting the tumour microenvironment and restoring immune recognition and immunogenicity. Epigenetic drugs such as DNA methyltransferase and histone deacetylase inhibitors can reverse immune suppression via several mechanisms such as enhancing expression of tumour-associated antigens, components of the antigen processing and presenting machinery pathways, immune checkpoint inhibitors, chemokines, and other immune-related genes. These discoveries have established a highly promising basis for studies using combined epigenetic and immunotherapeutic agents as anti-cancer therapies. In this review, we discuss the exciting role of epigenetic immunomodulation in tumour immune escape, emphasising its significance in priming and sensitising the host immune system to immunotherapies through mechanisms such as the activation of the viral defence pathway. With this background in mind, we highlight the promise of combined epigenetic therapy and immunotherapy, focusing on immune checkpoint blockade, to improve outcomes for patients with many different cancer types.
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Affiliation(s)
- Jennifer Dunn
- Health Research Institute, Faculty of Education, Science, Technology and Mathematics, University of Canberra, Bruce, ACT, 2601, Australia.
| | - Sudha Rao
- Health Research Institute, Faculty of Education, Science, Technology and Mathematics, University of Canberra, Bruce, ACT, 2601, Australia.
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3D Microfluidic model for evaluating immunotherapy efficacy by tracking dendritic cell behaviour toward tumor cells. Sci Rep 2017; 7:1093. [PMID: 28439087 PMCID: PMC5430848 DOI: 10.1038/s41598-017-01013-x] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 03/24/2017] [Indexed: 12/19/2022] Open
Abstract
Immunotherapy efficacy relies on the crosstalk within the tumor microenvironment between cancer and dendritic cells (DCs) resulting in the induction of a potent and effective antitumor response. DCs have the specific role of recognizing cancer cells, taking up tumor antigens (Ags) and then migrating to lymph nodes for Ag (cross)-presentation to naïve T cells. Interferon-α-conditioned DCs (IFN-DCs) exhibit marked phagocytic activity and the special ability of inducing Ag-specific T-cell response. Here, we have developed a novel microfluidic platform recreating tightly interconnected cancer and immune systems with specific 3D environmental properties, for tracking human DC behaviour toward tumor cells. By combining our microfluidic platform with advanced microscopy and a revised cell tracking analysis algorithm, it was possible to evaluate the guided efficient motion of IFN-DCs toward drug-treated cancer cells and the succeeding phagocytosis events. Overall, this platform allowed the dissection of IFN-DC-cancer cell interactions within 3D tumor spaces, with the discovery of major underlying factors such as CXCR4 involvement and underscored its potential as an innovative tool to assess the efficacy of immunotherapeutic approaches.
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Gul S. Epigenetic assays for chemical biology and drug discovery. Clin Epigenetics 2017; 9:41. [PMID: 28439316 PMCID: PMC5399855 DOI: 10.1186/s13148-017-0342-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Accepted: 04/12/2017] [Indexed: 12/27/2022] Open
Abstract
The implication of epigenetic abnormalities in many diseases and the approval of a number of compounds that modulate specific epigenetic targets in a therapeutically relevant manner in cancer specifically confirms that some of these targets are druggable by small molecules. Furthermore, a number of compounds are currently in clinical trials for other diseases including cardiovascular, neurological and metabolic disorders. Despite these advances, the approved treatments for cancer only extend progression-free survival for a relatively short time and being associated with significant side effects. The current clinical trials involving the next generation of epigenetic drugs may address the disadvantages of the currently approved epigenetic drugs. The identification of chemical starting points of many drugs often makes use of screening in vitro assays against libraries of synthetic or natural products. These assays can be biochemical (using purified protein) or cell-based (using for example, genetically modified, cancer cell lines or primary cells) and performed in microtiter plates, thus enabling a large number of samples to be tested. A considerable number of such assays are available to monitor epigenetic target activity, and this review provides an overview of drug discovery and chemical biology and describes assays that monitor activities of histone deacetylase, lysine-specific demethylase, histone methyltransferase, histone acetyltransferase and bromodomain. It is of critical importance that an appropriate assay is developed and comprehensively validated for a given drug target prior to screening in order to improve the probability of the compound progressing in the drug discovery value chain.
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Affiliation(s)
- Sheraz Gul
- Fraunhofer Institute for Molecular Biology and Applied Ecology - ScreeningPort, Schnackenburgallee 114, 22525 Hamburg, Germany
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Hamilton G, Rath B. Avelumab: combining immune checkpoint inhibition and antibody-dependent cytotoxicity. Expert Opin Biol Ther 2017; 17:515-523. [PMID: 28274143 DOI: 10.1080/14712598.2017.1294156] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Immune checkpoint inhibition holds great promise for selected tumors. The human monoclonal antibody (mAB) avelumab is directed to programmed death ligand-1 (PD-L1) and is supposed to inhibit the immunosuppressive PD-L1/PD-1 interaction and, furthermore, effect antibody-dependent cytotoxicity (ADCC) lysis of tumor cells. Areas covered: This article presents an overview of the current means to activate the antitumor immune defense by targeting PD-1 or PD-L1 with mABs and their possible role in ADCC-mediated tumor cell elimination. Expert opinion: Avelumab contains a Fc region which can bind cognate receptors on immune effector cells and induce ADCC-mediated tumor cell lysis, in contrast to other mABs directed to PD-1/PD-L1 which lack the ability to trigger ADCC due to belonging to the IgG4 subclass or possessing a mutated Fc region. Preclinical and clinical data indicate that avelumab can be safely administered to cancer patients with a toxicity profile comparable to other mABs and without lysis of PD-L1-positive activated immune cells. This antibody yielded durable responses in a phase II trial in advanced Merkel cell carcinoma patients. Tumor cell lysis by avelumab prevents cells from resorting to alternative checkpoints as shown by targeting PD-1 and the upregulation of TIM-3.
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Affiliation(s)
- Gerhard Hamilton
- a Department of Surgery , Medical University of Vienna , Vienna , Austria
| | - Barbara Rath
- a Department of Surgery , Medical University of Vienna , Vienna , Austria
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Zhao H, Ning S, Nolley R, Scicinski J, Oronsky B, Knox SJ, Peehl DM. The immunomodulatory anticancer agent, RRx-001, induces an interferon response through epigenetic induction of viral mimicry. Clin Epigenetics 2017; 9:4. [PMID: 28149332 PMCID: PMC5270305 DOI: 10.1186/s13148-017-0312-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 01/11/2017] [Indexed: 12/19/2022] Open
Abstract
Background RRx-001, a dinitroazetidine derivative, is a novel anticancer agent currently in phase II clinical trials. It mediates immunomodulatory effects either directly through polarization of tumor associated macrophages or indirectly through vascular normalization and increased T-lymphocyte infiltration. With multiple additional mechanisms of action including upregulation of oxidative stress, depletion of GSH and NADPH, anti-angiogenesis and epigenetic modulation, RRx-001 is being studied as a radio- and chemo-sensitizer to resensitize tumors to prior therapy and to prime tumors to respond to radiation, chemotherapy and immunotherapy in combination therapy studies. Here, we identified another mechanism, viral mimicry, which refers to the “unsilencing” of epigenetically repressed viral genes present in the tumor that provokes an immune response and may contribute to the anticancer activity of RRx-001. Results RRx-001 inhibited the growth of colon cancer cells (HCT 116) and decreased levels of the DNA methyltransferases DNMT1 and DNMT3a in a time and dose-dependent manner. Treatment of HCT 116 cells with 0.5 μM RRx-001 for 24 h significantly increased transcripts of interferon (IFN)-responsive genes and this induction was sustained for up to 4 weeks after transient exposure to RRx-001. ELISA assays showed that RRx-001 increased secretion of type I and III IFNs by HCT 116 cells, and these IFNs were confirmed to be bioactive. Transcription of endogenous retrovirus ERV-Fc2 and LTRs from the ERV-L family (MLT2B4 and MLT1C49) was induced by RRx-001. The induction of ERV-Fc2-env was through demethylation of ERV-Fc2 LTR as determined by methylation-specific polymerase chain reaction and combined bisulfite restriction analysis. Immunofluorescence staining with J2 antibody confirmed induction of double-stranded RNA. Conclusions Transient exposure of HCT 116 cells to low-dose RRx-001 induced transcription of silenced retroviral genes present in the cancer cell DNA with subsequent synthesis of IFN in response to this “pseudo-pathogenic” stimulus, mimicking an antiviral defense. RRx-001-mediated IFN induction may have the potential to improve the efficacy of immunotherapies as well as radiotherapy, standard chemotherapies and molecularly targeted agents when used in combination. The striking safety profile of RRx-001 in comparison to other more toxic epigenetic and immunomodulatory agents such as azacitidine makes it a leading candidate for such clinical applications.
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Affiliation(s)
- Hongjuan Zhao
- Department of Urology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 USA
| | - Shoucheng Ning
- Department of Radiation Oncology, School of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305 USA
| | - Rosalie Nolley
- Department of Urology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 USA
| | - Jan Scicinski
- EpicentRx, Inc., 800W El Camino Real, Suite 180, Mountain View, CA 94040 USA
| | - Bryan Oronsky
- EpicentRx, Inc., 800W El Camino Real, Suite 180, Mountain View, CA 94040 USA
| | - Susan J Knox
- Department of Radiation Oncology, School of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305 USA
| | - Donna M Peehl
- Department of Urology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305 USA
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Castillo-Aguilera O, Depreux P, Halby L, Arimondo PB, Goossens L. DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge. Biomolecules 2017; 7:biom7010003. [PMID: 28067760 PMCID: PMC5372715 DOI: 10.3390/biom7010003] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 12/08/2016] [Accepted: 12/12/2016] [Indexed: 12/22/2022] Open
Abstract
Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action.
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Affiliation(s)
- Omar Castillo-Aguilera
- Univ. Lille, ICPAL, EA 7365-GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, 3 rue du Pr. Laguesse, F-59000 Lille, France.
| | - Patrick Depreux
- Univ. Lille, ICPAL, EA 7365-GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, 3 rue du Pr. Laguesse, F-59000 Lille, France.
| | - Ludovic Halby
- FRE3600 Epigenetic Targeting of Cancer, CNRS, 31035 Toulouse, France.
| | - Paola B Arimondo
- FRE3600 Epigenetic Targeting of Cancer, CNRS, 31035 Toulouse, France.
- Churchill College, Cambridge CB3 0DS, UK.
| | - Laurence Goossens
- Univ. Lille, ICPAL, EA 7365-GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, 3 rue du Pr. Laguesse, F-59000 Lille, France.
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Hepatoepigenetic Alterations in Viral and Nonviral-Induced Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2016; 2016:3956485. [PMID: 28105421 PMCID: PMC5220417 DOI: 10.1155/2016/3956485] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 11/30/2016] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major public health concern and one of the leading causes of tumour-related deaths worldwide. Extensive evidence endorses that HCC is a multifactorial disease characterised by hepatic cirrhosis mostly associated with chronic inflammation and hepatitis B/C viral infections. Interaction of viral products with the host cell machinery may lead to increased frequency of genetic and epigenetic aberrations that cause harmful alterations in gene transcription. This may provide a progressive selective advantage for neoplastic transformation of hepatocytes associated with phenotypic heterogeneity of intratumour HCC cells, thus posing even more challenges in HCC treatment development. Epigenetic aberrations involving DNA methylation, histone modifications, and noncoding miRNA dysregulation have been shown to be intimately linked with and play a critical role in tumour initiation, progression, and metastases. The current review focuses on the aberrant hepatoepigenetics events that play important roles in hepatocarcinogenesis and their utilities in the development of HCC therapy.
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Lucarini V, Buccione C, Ziccheddu G, Peschiaroli F, Sestili P, Puglisi R, Mattia G, Zanetti C, Parolini I, Bracci L, Macchia I, Rossi A, D'Urso MT, Macchia D, Spada M, De Ninno A, Gerardino A, Mozetic P, Trombetta M, Rainer A, Businaro L, Schiavoni G, Mattei F. Combining Type I Interferons and 5-Aza-2'-Deoxycitidine to Improve Anti-Tumor Response against Melanoma. J Invest Dermatol 2016; 137:159-169. [PMID: 27623509 DOI: 10.1016/j.jid.2016.08.024] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 07/28/2016] [Accepted: 08/18/2016] [Indexed: 10/21/2022]
Abstract
Resistance to IFN-I-induced antineoplastic effects has been reported in many tumors and arises, in part, from epigenetic silencing of IFN-stimulated genes by DNA methylation. We hypothesized that restoration of IFN-stimulated genes by co-administration of the demethylating drug 5-aza-2'-deoxycitidine (decitabine [DAC]) may enhance the susceptibility to IFN-I-mediated antitumoral effects in melanoma. We show that combined administration of IFN-I and DAC significantly inhibits the growth of murine and human melanoma cells, both in vitro and in vivo. Compared with controls, DAC/IFN-I-treated melanoma cells exhibited reduced cell growth, augmented apoptosis, and diminished migration. Moreover, IFN-I and DAC synergized to suppress the growth of three-dimensional human melanoma spheroids, altering tumor architecture. These direct antitumor effects correlated with induction of the IFN-stimulated gene Mx1. In vivo, DAC/IFN-I significantly reduced melanoma growth via stimulation of adaptive immunity, promoting tumor-infiltrating CD8+ T cells while inhibiting the homing of immunosuppressive CD11b+ myeloid cells and regulatory T cells. Accordingly, exposure of human melanoma cells to DAC/IFN-I induced the recruitment of immune cells toward the tumor in a Matrigel (Corning Life Sciences, Kennebunkport, ME)-based microfluidic device. Our findings underscore a beneficial effect of DAC plus IFN-I combined treatment against melanoma through both direct and immune-mediated anti-tumor effects.
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Affiliation(s)
- Valeria Lucarini
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Carla Buccione
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Giovanna Ziccheddu
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Francesca Peschiaroli
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Paola Sestili
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Rossella Puglisi
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Gianfranco Mattia
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Cristiana Zanetti
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Isabella Parolini
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Laura Bracci
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Iole Macchia
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Alessandra Rossi
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Maria Teresa D'Urso
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Daniele Macchia
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Massimo Spada
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Adele De Ninno
- Institute for Photonics and Nanotechnologies, Italian National Research Council, Rome, Italy
| | - Annamaria Gerardino
- Institute for Photonics and Nanotechnologies, Italian National Research Council, Rome, Italy
| | - Pamela Mozetic
- Unit of Tissue Engineering, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, Rome, Italy
| | - Marcella Trombetta
- Unit of Tissue Engineering, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, Rome, Italy
| | - Alberto Rainer
- Unit of Tissue Engineering, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, Rome, Italy
| | - Luca Businaro
- Institute for Photonics and Nanotechnologies, Italian National Research Council, Rome, Italy; UCBM-CNR Joint Lab for Nanotechnologies for the Life Sciences, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Giovanna Schiavoni
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Fabrizio Mattei
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
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Decitabine Treatment of Glioma-Initiating Cells Enhances Immune Recognition and Killing. PLoS One 2016; 11:e0162105. [PMID: 27579489 PMCID: PMC5007044 DOI: 10.1371/journal.pone.0162105] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 08/17/2016] [Indexed: 12/30/2022] Open
Abstract
Malignant gliomas are aggressive brain tumours with very poor prognosis. The majority of glioma cells are differentiated (glioma-differentiated cells: GDCs), whereas the smaller population (glioma-initiating cells, GICs) is undifferentiated and resistant to conventional therapies. Therefore, to better target this pool of heterogeneous cells, a combination of diverse therapeutic approaches is envisaged. Here we investigated whether the immunosensitising properties of the hypomethylating agent decitabine can be extended to GICs. Using the murine GL261 cell line, we demonstrate that decitabine augments the expression of the death receptor FAS both on GDCs and GICs. Interestingly, it had a higher impact on GICs and correlated with an enhanced sensitivity to FASL-mediated cell death. Moreover, the expression of other critical molecules involved in cognate recognition by cytotoxic T lymphocytes, MHCI and ICAM-1, was upregulated by decitabine treatment. Consequently, T-cell mediated killing of both GDCs and GICs was enhanced, as was T cell proliferation after reactivation. Overall, although GICs are described to resist classical therapies, our study shows that hypomethylating agents have the potential to enhance glioma cell recognition and subsequent destruction by immune cells, regardless of their differentiation status. These results support the development of combinatorial treatment modalities including epigenetic modulation together with immunotherapy in order to treat heterogenous malignancies such as glioblastoma.
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Cives M, Simone V, Rizzo FM, Silvestris F. NETs: organ-related epigenetic derangements and potential clinical applications. Oncotarget 2016; 7:57414-57429. [PMID: 27418145 PMCID: PMC5302998 DOI: 10.18632/oncotarget.10598] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 06/30/2016] [Indexed: 12/15/2022] Open
Abstract
High-throughput next-generation sequencing methods have recently provided a detailed picture of the genetic landscape of neuroendocrine tumors (NETs), revealing recurrent mutations of chromatin-remodeling genes and little-to-no pathogenetic role for oncogenes commonly mutated in cancer. Concurrently, multiple epigenetic modifications have been described across the whole spectrum of NETs, and their putative function as tumorigenic drivers has been envisaged. As result, it is still unclear whether or not NETs are epigenetically-driven, rather than genetically-induced malignancies. Although the NET epigenome profiling has led to the identification of molecularly-distinct tumor subsets, validation studies in larger cohorts of patients are needed to translate the use of NET epitypes in clinical practice. In the precision medicine era, recognition of subpopulations of patients more likely to respond to therapeutic agents is critical, and future studies testing epigenetic biomarkers are therefore awaited. Restoration of the aberrant chromatin remodeling machinery is an attractive approach for future treatment of cancer and in several hematological malignancies a few epigenetic agents have been already approved. Although clinical outcomes of epigenetic therapies in NETs have been disappointing so far, further clinical trials are required to investigate the efficacy of these drugs. In this context, given the immune-stimulating effects of epidrugs, combination therapies with immune checkpoint inhibitors should be tested. In this review, we provide an overview of the epigenetic changes in both hereditary and sporadic NETs of the gastroenteropancreatic and bronchial tract, focusing on their diagnostic, prognostic and therapeutic implications.
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Affiliation(s)
- Mauro Cives
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| | - Valeria Simone
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| | - Francesca Maria Rizzo
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
| | - Franco Silvestris
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy
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Kunert A, van Brakel M, van Steenbergen-Langeveld S, da Silva M, Coulie PG, Lamers C, Sleijfer S, Debets R. MAGE-C2-Specific TCRs Combined with Epigenetic Drug-Enhanced Antigenicity Yield Robust and Tumor-Selective T Cell Responses. THE JOURNAL OF IMMUNOLOGY 2016; 197:2541-52. [PMID: 27489285 DOI: 10.4049/jimmunol.1502024] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 07/03/2016] [Indexed: 01/22/2023]
Abstract
Adoptive T cell therapy has shown significant clinical success for patients with advanced melanoma and other tumors. Further development of T cell therapy requires improved strategies to select effective, yet nonself-reactive, TCRs. In this study, we isolated 10 TCR sequences against four MAGE-C2 (MC2) epitopes from melanoma patients who showed clinical responses following vaccination that were accompanied by significant frequencies of anti-MC2 CD8 T cells in blood and tumor without apparent side effects. We introduced these TCRs into T cells, pretreated tumor cells of different histological origins with the epigenetic drugs azacytidine and valproate, and tested tumor and self-reactivities of these TCRs. Pretreatment of tumor cells upregulated MC2 gene expression and enhanced recognition by T cells. In contrast, a panel of normal cell types did not express MC2 mRNA, and similar pretreatment did not result in recognition by MC2-directed T cells. Interestingly, the expression levels of MC2, but not those of CD80, CD86, or programmed death-ligand 1 or 2, correlated with T cell responsiveness. One of the tested TCRs consistently recognized pretreated MC2(+) cell lines from melanoma, head and neck, bladder, and triple-negative breast cancers but showed no response to MHC-eluted peptides or peptides highly similar to MC2. We conclude that targeting MC2 Ag, combined with epigenetic drug-enhanced antigenicity, allows for significant and tumor-selective T cell responses.
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Affiliation(s)
- Andre Kunert
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and
| | - Mandy van Brakel
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and
| | - Sabine van Steenbergen-Langeveld
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and
| | - Marvin da Silva
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and
| | - Pierre G Coulie
- de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Cor Lamers
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and
| | - Stefan Sleijfer
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and
| | - Reno Debets
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, the Netherlands; and
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Methyltransferase inhibitors for modulation of the epigenome and beyond. Curr Opin Chem Biol 2016; 33:81-7. [DOI: 10.1016/j.cbpa.2016.05.030] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 05/17/2016] [Accepted: 05/30/2016] [Indexed: 12/20/2022]
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Xu P, Hu G, Luo C, Liang Z. DNA methyltransferase inhibitors: an updated patent review (2012-2015). Expert Opin Ther Pat 2016; 26:1017-30. [PMID: 27376512 DOI: 10.1080/13543776.2016.1209488] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
INTRODUCTION DNA methyltransferases (DNMTs), important enzymes involved in epigenetic regulation of gene expression, represent promising targets in cancer therapy. DNMT inhibitors (DNMTi), which can modulate the aberrant DNA methylation pattern in a reversible way via inhibiting DNMT activity, have attracted significant attention in recent years. AREAS COVERED This review outlines the newly patented inhibitors targeting DNMTs, mainly incorporating small molecular inhibitors and oligonucleotide derivatives. The chemical structures, biological activity, and the encouraging clinical research in progress are delineated in detail. EXPERT OPINION Two drugs, azacitidine and decitabine, have evidently shown efficacy in hematologic malignancies, yet do not work well on solid tumors, have low specificity, substantial toxicity, and poor bioavailability. With the rapid advancement in systems biology, drug combinations, such as DNMTi, in conjugation with histone deacetylase inhibitors (HDACi) or immunotherapy, probably serve as an efficient way of implementing epigenetic therapy. Meanwhile, the resolved autoinhibitory structures of DNMTs afford a novel strategy for targeting the protein-protein interface involved in the autoinhi-bitory interactions. The molecular mechanism underlying the conformational transitions would also shed new light on the design of allosteric inhibitors. Both strategies would produce inhibitors with more selectivity compared to nucleotide derivatives.
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Affiliation(s)
- Pan Xu
- a Center for Systems Biology , Soochow University , Jiangsu , China.,b Shanghai Institute of Materia Medica, State Key Laboratory of Drug Research , Chinese Academy of Sciences , Shanghai , China
| | - Guang Hu
- a Center for Systems Biology , Soochow University , Jiangsu , China
| | - Cheng Luo
- b Shanghai Institute of Materia Medica, State Key Laboratory of Drug Research , Chinese Academy of Sciences , Shanghai , China
| | - Zhongjie Liang
- a Center for Systems Biology , Soochow University , Jiangsu , China
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TCR-engineered T cells to treat tumors: Seeing but not touching? Semin Immunol 2016; 28:10-21. [PMID: 26997556 DOI: 10.1016/j.smim.2016.03.002] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 03/02/2016] [Accepted: 03/04/2016] [Indexed: 12/17/2022]
Abstract
Adoptive transfer of T cells gene-engineered with T cell receptors (TCRs) has proven its feasibility and therapeutic potential in the treatment of malignant tumors. To ensure further clinical development of TCR gene therapy, it is necessary to accurately select TCRs that demonstrate antigen-selective responses that are restricted to tumor cells and, at the same time, include strategies that restore or enhance the entry, migration and local accumulation of T cells in tumor tissues. Here, we present the current standing of TCR-engineered T cell therapy, discuss and propose procedures to select TCRs as well as strategies to sensitize the tumor to T cell trafficking, and provide a rationale for combination therapies with TCR-engineered T cells.
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Gonzalez-Cao M, Iduma P, Karachaliou N, Santarpia M, Blanco J, Rosell R. Human endogenous retroviruses and cancer. Cancer Biol Med 2016; 13:483-488. [PMID: 28154780 PMCID: PMC5250606 DOI: 10.20892/j.issn.2095-3941.2016.0080] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Human endogenous retroviruses (HERVs) are retroviruses that infected human genome millions of years ago and have persisted throughout human evolution. About 8% of our genome is composed of HERVs, most of which are nonfunctional because of epigenetic control or deactivating mutations. However, a correlation between HERVs and human cancer has been described and many tumors, such as melanoma, breast cancer, germ cell tumors, renal cancer or ovarian cancer, express HERV proteins, mainly HERV-K (HML6) and HERV-K (HML2). Although the causative role of HERVs in cancer is controversial, data from animal models demonstrated that endogenous retroviruses are potentially oncogenic. HERV protein expression in human cells generates an immune response by activating innate and adaptive immunities. Some HERV-derived peptides have antigenic properties. For example, HERV-K (HML-6) encodes the HER-K MEL peptide recognized by CD8+ lymphocytes. In addition, HERVs are two-edged immunomodulators. HERVs show immunosuppressive activity. The presence of genomic retroviral elements in host-cell cytosol may activate an interferon type I response. Therefore, targeting HERVs through cellular vaccines or immunomodulatory drugs combined with checkpoint inhibitors is attracting interest because they could be active in human tumors.
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Affiliation(s)
- María Gonzalez-Cao
- Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona 08028, Spain
| | - Paola Iduma
- AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Badalona 08028, Spain
| | - Niki Karachaliou
- Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona 08028, Spain
| | - Mariacarmela Santarpia
- Medical Oncology Unit, Human Pathology Department, University of Messina, Messina, 98122, Italy
| | - Julià Blanco
- AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Badalona 08028, Spain; UVIC-UCC, Catalunya 08500, Spain
| | - Rafael Rosell
- Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona 08028, Spain; Cancer Biology & Precision Medicine Program, Catalan Institute of Oncology, Germans Trias I Pujol Health Sciences Institute and Hospital, Campus Can Ruti, Badalona, 08916, Spain; Fundación Molecular Oncology Research, Barcelona 08028, Spain
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