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Occhipinti M, Brambilla M, Di Liello R, Ambrosini P, Lobianco L, Leporati R, Salvarezza M, Vitiello F, Marchesi S, Manglaviti S, Beninato T, Mazzeo L, Proto C, Prelaj A, Ferrara R, Della Corte CM, Lo Russo G, de Braud F, Ganzinelli M, Viscardi G. Unleashing precision: A review of targeted approaches in pleural mesothelioma. Crit Rev Oncol Hematol 2024; 203:104481. [PMID: 39159705 DOI: 10.1016/j.critrevonc.2024.104481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 08/21/2024] Open
Abstract
This review delves into the intricate landscape of pleural mesothelioma (PM), emphasizing the need for nuanced therapeutic strategies. While platinum-based chemotherapy remains a cornerstone, the advent of immune checkpoint inhibitors (ICIs), notably through the Checkmate 743 trial, has reshaped treatment paradigms. Challenges persist due to patient heterogeneity and a lack of specific biomarkers. Targeting genotypic and phenotypic alterations emerges as a promising avenue, demanding precision oncology in this rare disease. CDKN2A loss, prevalent in PM, may respond to CDK4/6 inhibitors. Defects in MMR and HR suggest tailored approaches with ICI or PARP inhibitors, respectively. Ongoing trials explore novel inhibitors and promising targets like mesothelin. Implementing these strategies requires overcoming challenges in patient selection, combination therapies, biomarker identification, and cost considerations. Collaboration is crucial for transforming these insights into impactful clinical interventions, heralding the era of personalized and precision medicine for PM.
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Affiliation(s)
- Mario Occhipinti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Marta Brambilla
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
| | | | - Paolo Ambrosini
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Lorenzo Lobianco
- Medical Oncology, Precision Medicine Department, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Rita Leporati
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Maria Salvarezza
- Medical Oncology, Precision Medicine Department, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Fabiana Vitiello
- Medical Oncology Unit, Ospedale Monaldi, AORN Ospedali dei Colli, Naples, Italy
| | - Silvia Marchesi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Sara Manglaviti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Teresa Beninato
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Laura Mazzeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Claudia Proto
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Arsela Prelaj
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Department of Electronics, Information and Bioengineering, Polytechnic University of Milan, Milan, Italy
| | - Roberto Ferrara
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | | | - Giuseppe Lo Russo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Filippo de Braud
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Monica Ganzinelli
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Giuseppe Viscardi
- Medical Oncology Unit, Ospedale Monaldi, AORN Ospedali dei Colli, Naples, Italy
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Prabhakaran R, Thamarai R, Sivasamy S, Dhandayuthapani S, Batra J, Kamaraj C, Karthik K, Shah MA, Mallik S. Epigenetic frontiers: miRNAs, long non-coding RNAs and nanomaterials are pioneering to cancer therapy. Epigenetics Chromatin 2024; 17:31. [PMID: 39415281 PMCID: PMC11484394 DOI: 10.1186/s13072-024-00554-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 09/25/2024] [Indexed: 10/18/2024] Open
Abstract
Cancer has arisen from both genetic mutations and epigenetic changes, making epigenetics a crucial area of research for innovative cancer prevention and treatment strategies. This dual perspective has propelled epigenetics into the forefront of cancer research. This review highlights the important roles of DNA methylation, histone modifications and non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs, which are key regulators of cancer-related gene expression. It explores the potential of epigenetic-based therapies to revolutionize patient outcomes by selectively modulating specific epigenetic markers involved in tumorigenesis. The review examines promising epigenetic biomarkers for early cancer detection and prognosis. It also highlights recent progress in oligonucleotide-based therapies, including antisense oligonucleotides (ASOs) and antimiRs, to precisely modulate epigenetic processes. Furthermore, the concept of epigenetic editing is discussed, providing insight into the future role of precision medicine for cancer patients. The integration of nanomedicine into cancer therapy has been explored and offers innovative approaches to improve therapeutic efficacy. This comprehensive review of recent advances in epigenetic-based cancer therapy seeks to advance the field of precision oncology, ultimately culminating in improved patient outcomes in the fight against cancer.
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Affiliation(s)
- Rajkumar Prabhakaran
- Central Research Facility, Santosh Deemed to be University, Ghaziabad, UP, India
| | - Rajkumar Thamarai
- UGC Dr. D.S. Kothari Postdoctoral Fellow, Department of Animal Science, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu, 627012, India
| | - Sivabalan Sivasamy
- Central Research Facility, Santosh Deemed to be University, Ghaziabad, UP, India
| | | | - Jyoti Batra
- Central Research Facility, Santosh Deemed to be University, Ghaziabad, UP, India.
| | - Chinnaperumal Kamaraj
- Interdisciplinary Institute of Indian System of Medicine, Directorate of Research, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India.
| | - Krishnasamy Karthik
- Department of Mechanical Engineering, Vel Tech Rangarajan Dr. Sagunthala R&D Institute of Science and Technology, Chennai, India
| | - Mohd Asif Shah
- Department of Economics, Kardan University, Parwane Du, 1001, Kabul, Afghanistan.
- Division of Research and Development, Lovely Professional University, Phagwara, Punjab, 144001, India.
- Centre of Research Impact and Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, 140401, India.
| | - Saurav Mallik
- Department of Environmental Health, Harvard T H Chan School of Public Health, Boston, Massachusetts, 02115, United States.
- Department of Pharmacology & Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
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Zaalberg A, Pottendorfer E, Zwart W, Bergman AM. It Takes Two to Tango: The Interplay between Prostate Cancer and Its Microenvironment from an Epigenetic Perspective. Cancers (Basel) 2024; 16:294. [PMID: 38254784 PMCID: PMC10813511 DOI: 10.3390/cancers16020294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/28/2023] [Accepted: 12/28/2023] [Indexed: 01/24/2024] Open
Abstract
Prostate cancer is the second most common cancer in men worldwide and is associated with high morbidity and mortality. Consequently, there is an urgent unmet need for novel treatment avenues. In addition to somatic genetic alterations, deviations in the epigenetic landscape of cancer cells and their tumor microenvironment (TME) are critical drivers of prostate cancer initiation and progression. Unlike genomic mutations, epigenetic modifications are potentially reversible. Therefore, the inhibition of aberrant epigenetic modifications represents an attractive and exciting novel treatment strategy for castration-resistant prostate cancer patients. Moreover, drugs targeting the epigenome also exhibit synergistic interactions with conventional therapeutics by directly enhancing their anti-tumorigenic properties by "priming" the tumor and tumor microenvironment to increase drug sensitivity. This review summarizes the major epigenetic alterations in prostate cancer and its TME, and their involvement in prostate tumorigenesis, and discusses the impact of epigenome-targeted therapies.
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Affiliation(s)
- Anniek Zaalberg
- Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; (A.Z.); (E.P.)
| | - Elisabeth Pottendorfer
- Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; (A.Z.); (E.P.)
| | - Wilbert Zwart
- Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; (A.Z.); (E.P.)
- Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands
- Oncode Institute
| | - Andries M. Bergman
- Division of Oncogenomics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; (A.Z.); (E.P.)
- Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Rocha GIY, Gomes JEM, Leite ML, da Cunha NB, Costa FF. Epigenome-Driven Strategies for Personalized Cancer Immunotherapy. Cancer Manag Res 2023; 15:1351-1367. [PMID: 38058537 PMCID: PMC10697012 DOI: 10.2147/cmar.s272031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 11/19/2023] [Indexed: 12/08/2023] Open
Abstract
Fighting cancer remains one of the greatest challenges for science in the 21st century. Advances in immunotherapy against different types of cancer have greatly contributed to the treatment, remission, and cure of patients. In this context, knowledge of epigenetic phenomena, their relationship with tumor cells and how the immune system can be epigenetically modulated represent some of the greatest advances in the development of anticancer therapies. Epigenetics is a rapidly growing field that studies how environmental factors can affect gene expression without altering DNA sequence. Epigenomic changes include DNA methylation, histone modifications, and non-coding RNA regulation, which impact cellular function. Epigenetics has shown promise in developing cancer therapies, such as immunotherapy, which aims to stimulate the immune system to attack cancer cells. For example, PD-1 and PD-L1 are biomarkers that regulate the immune response to cancer cells and recent studies have shown that epigenetic modifications can affect their expression, potentially influencing the efficacy of immunotherapy. New therapies targeting epigenetic modifications, such as histone deacetylases and DNA methyltransferases, are being developed for cancer treatment, and some have shown promise in preclinical studies and clinical trials. With growing understanding of epigenetic regulation, we can expect more personalized and effective cancer immunotherapies in the future. This review highlights key advances in the use of epigenetic and epigenomic tools and modern immuno-oncology strategies to treat several types of tumors.
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Affiliation(s)
| | | | - Michel Lopes Leite
- Genomic Sciences and Biotechnology Program, Catholic University of Brasilia, Brasília, DF, Brazil
- Department of Cell Biology, Institute of Biological Sciences, Campus Darcy Ribeiro, University of Brasilia (UnB), Brasília, DF, Brazil
| | - Nicolau B da Cunha
- Genomic Sciences and Biotechnology Program, Catholic University of Brasilia, Brasília, DF, Brazil
- Faculty of Agronomy and Veterinary Medicine (FAV), Campus Darcy Ribeiro, University of Brasilia (UnB), Brasília, DF, Brazil
- Graduate Program in Agronomy, Campus Darcy Ribeiro, University of Brasilia (UnB), Brasília, DF, Brazil
| | - Fabricio F Costa
- Genomic Sciences and Biotechnology Program, Catholic University of Brasilia, Brasília, DF, Brazil
- Cancer Biology and Epigenomics Program, Northwestern University’s Feinberg School of Medicine, Chicago, IL, USA
- Genomic Enterprise, San FranciscoCA, USA
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Liang Y, Wang L, Ma P, Ju D, Zhao M, Shi Y. Enhancing anti-tumor immune responses through combination therapies: epigenetic drugs and immune checkpoint inhibitors. Front Immunol 2023; 14:1308264. [PMID: 38077327 PMCID: PMC10704038 DOI: 10.3389/fimmu.2023.1308264] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/06/2023] [Indexed: 12/18/2023] Open
Abstract
Epigenetic mechanisms are processes that affect gene expression and cellular functions without involving changes in the DNA sequence. This abnormal or unstable expression of genes regulated by epigenetics can trigger cancer and other various diseases. The immune cells involved in anti-tumor responses and the immunogenicity of tumors may also be affected by epigenomic changes. This holds significant implications for the development and application of cancer immunotherapy, epigenetic therapy, and their combined treatments in the fight against cancer. We provide an overview of recent research literature focusing on how epigenomic changes in immune cells influence immune cell behavior and function, as well as the immunogenicity of cancer cells. And the combined utilization of epigenetic medications with immune checkpoint inhibitors that focus on immune checkpoint molecules [e.g., Programmed Death 1 (PD-1), Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4), T cell Immunoglobulin and Mucin Domain (TIM-3), Lymphocyte Activation Gene-3 (LAG-3)] present in immune cells and stromal cells associated with tumors. We highlight the potential of small-molecule inhibitors targeting epigenetic regulators to amplify anti-tumor immune responses. Moreover, we discuss how to leverage the intricate relationship between cancer epigenetics and cancer immunology to create treatment regimens that integrate epigenetic therapies with immunotherapies.
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Affiliation(s)
- Ying Liang
- Precision Pharmacy and Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Lingling Wang
- Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan Wuchang Hospital, Wuhan, China
| | - Peijun Ma
- Clinical Laboratory, Shanghai Mental Health Center, Shanghai, China
| | - Dongen Ju
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Minggao Zhao
- Precision Pharmacy and Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yun Shi
- Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA, United States
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Amaro A, Reggiani F, Fenoglio D, Gangemi R, Tosi A, Parodi A, Banelli B, Rigo V, Mastracci L, Grillo F, Cereghetti A, Tastanova A, Ghosh A, Sallustio F, Emionite L, Daga A, Altosole T, Filaci G, Rosato A, Levesque M, Maio M, Pfeffer U, Croce M. Guadecitabine increases response to combined anti-CTLA-4 and anti-PD-1 treatment in mouse melanoma in vivo by controlling T-cells, myeloid derived suppressor and NK cells. J Exp Clin Cancer Res 2023; 42:67. [PMID: 36934257 PMCID: PMC10024396 DOI: 10.1186/s13046-023-02628-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/21/2023] [Indexed: 03/20/2023] Open
Abstract
BACKGROUND The combination of Programmed Cell Death 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) blockade has dramatically improved the overall survival rate for malignant melanoma. Immune checkpoint blockers (ICBs) limit the tumor's immune escape yet only for approximately a third of all tumors and, in most cases, for a limited amount of time. Several approaches to overcome resistance to ICBs are being investigated among which the addition of epigenetic drugs that are expected to act on both immune and tumor cells. Guadecitabine, a dinucleotide prodrug of a decitabine linked via phosphodiester bond to a guanosine, showed promising results in the phase-1 clinical trial, NIBIT-M4 (NCT02608437). METHODS We used the syngeneic B16F10 murine melanoma model to study the effects of immune checkpoint blocking antibodies against CTLA-4 and PD-1 in combination, with and without the addition of Guadecitabine. We comprehensively characterized the tumor's and the host's responses under different treatments by flow cytometry, multiplex immunofluorescence and methylation analysis. RESULTS In combination with ICBs, Guadecitabine significantly reduced subcutaneous tumor growth as well as metastases formation compared to ICBs and Guadecitabine treatment. In particular, Guadecitabine greatly enhanced the efficacy of combined ICBs by increasing effector memory CD8+ T cells, inducing effector NK cells in the spleen and reducing tumor infiltrating regulatory T cells and myeloid derived suppressor cells (MDSC), in the tumor microenvironment (TME). Guadecitabine in association with ICBs increased serum levels of IFN-γ and IFN-γ-induced chemokines with anti-angiogenic activity. Guadecitabine led to a general DNA-demethylation, in particular of sites of intermediate methylation levels. CONCLUSIONS These results indicate Guadecitabine as a promising epigenetic drug to be added to ICBs therapy.
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Affiliation(s)
- Adriana Amaro
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
| | - Francesco Reggiani
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
| | - Daniela Fenoglio
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
- Department of Internal Medicine, University of Genova, Genova, Italy
| | - Rosaria Gangemi
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
| | - Anna Tosi
- Immunology and Molecular Oncology Diagnostics, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | - Alessia Parodi
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
| | - Barbara Banelli
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
| | - Valentina Rigo
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
| | - Luca Mastracci
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
| | - Federica Grillo
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
| | - Alessandra Cereghetti
- Department of Dermatology, University of Zurich, University Hospital of Zurich, Zurich, Switzerland
| | - Aizhan Tastanova
- Department of Dermatology, University of Zurich, University Hospital of Zurich, Zurich, Switzerland
| | - Adhideb Ghosh
- Functional Genomics Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
| | - Fabio Sallustio
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Laura Emionite
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
| | - Antonio Daga
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
| | - Tiziana Altosole
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
| | - Gilberto Filaci
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
- Department of Internal Medicine, University of Genova, Genova, Italy
| | - Antonio Rosato
- Immunology and Molecular Oncology Diagnostics, Istituto Oncologico Veneto IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Mitchell Levesque
- Department of Dermatology, University of Zurich, University Hospital of Zurich, Zurich, Switzerland
| | | | - Ulrich Pfeffer
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy.
| | - Michela Croce
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genova, Italy
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Ma M, Li J, Zeng Z, Zheng Z, Kang W. Integrated analysis from multicentre studies identities m7G-related lncRNA-derived molecular subtypes and risk stratification systems for gastric cancer. Front Immunol 2023; 14:1096488. [PMID: 36936957 PMCID: PMC10017847 DOI: 10.3389/fimmu.2023.1096488] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Abstract
Introduction Gastric cancer (GC) is the fourth leading cause of cancer death worldwide. Due to the lack of effective chemotherapy methods for advanced gastric cancer and poor prognosis, the emergence of immunotherapy has brought new hope to gastric cancer. Further research is needed to improve the response rate to immunotherapy and identify the populations with potential benefits of immunotherapy. It is unclear whether m7G-related lncRNAs influence tumour immunity and the prognosis of immunotherapy. Methods This study evaluated 29 types of immune cells and immune functions in gastric cancer patients, and m7G-related lncRNAs and their molecular subtypes were identified. In addition, we also studied the biological function characteristics of m7G-related lncRNA molecular subtypes. Finally, the patient's risk score was calculated based on m7G-related lncRNAs, and a nomogram of staging and risk groups was established to predict the prognosis. For experimental verification, RT-qPCR were preformed from the native cohort. Results After identifying m7G-related lncRNAs and their molecular subtypes, we found three molecular subtypes, the B subtype had the highest level of infiltration, and the B subtype may benefit more from immunotherapy. We divided GC patients into two regulator subtypes based on biological function. The two subtypes have significant immunological differences and can be used to judge ICI treatment. We established a risk score formula based on five lncRNAs, including LINC00924, LINC00944, LINC00865, LINC00702, and ZFAS1. Patients with poor prognoses were closely related to patients in the high-risk group. After comprehensive analysis of different risk groups, the efficacy of the high-risk group on bleomycin, cisplatin, docetaxel, doxorubicin and etoposide was better than that of the low-risk group, suggesting that risk subgroups based on risk scores play a guiding role in chemotherapy and that the high-risk group may benefit more from immunotherapy. RT-qPCR results showed that LINC00924, LINC00944, and LINC00865 were highly expressed in tumour tissues, while LINC00702 and ZFAS1 were expressed at low levels in tumour tissues. Discussion In conclusion, we were the first to discover that m7G-related lncRNAs play a vital role in the tumour immune microenvironment of gastric cancer, and a risk prediction model was established to identify patients with potential benefits from immunotherapy and predict the prognosis of GC patients.
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Li Q, Han J, Yang Y, Chen Y. PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy. Front Immunol 2022; 13:1070961. [PMID: 36601120 PMCID: PMC9806143 DOI: 10.3389/fimmu.2022.1070961] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has a high prevalence and mortality rate worldwide. Sorafenib monotherapy has been the standard of first-line treatment for advanced HCC for a long time, but there are still many shortcomings. In recent years, with the deepening of research on tumor immune microenvironment, researchers have begun to explore new approaches in immunotherapy, and the introduction of immune checkpoint inhibitors has brought fundamental changes to the treatment of HCC. Programmed cell death protein 1 (PD-1) is an immune checkpoint molecule that plays an important role in down-regulating immune system function and promoting tolerance. Programmed cell death ligand 1 (PDL-1) is involved in tumor immune evasion by binding to PD-1, resulting in failure of treatment. Currently, immunotherapy targeting the PD-1/PD-L1 axis has achieved unprecedented success in HCC, but it also faces great challenges, with its low remission rate still to be solved. For most patients with HCC, the PD-1/PD-L1 pathway is not the only rate limiting factor of antitumor immunity, and blocking only the PD-1/PD-L1 axis is not enough to stimulate an effective antitumor immune response; thus, combination therapy may be a better option. In this study, changes in the immune microenvironment of HCC patients were reviewed to clarify the feasibility of anti-PD-1/PD-L1 therapy, and a series of monotherapy and combination therapy clinical trials were summarized to verify the safety and efficacy of this newly developed treatment in patients with advanced HCC. Furthermore, we focused on hyperprogressive disease and drug resistance to gain a better understanding of PD-1/PD-L1 blockade as a promising treatment.
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Affiliation(s)
- Qian Li
- Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jingjing Han
- Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yonglin Yang
- Department of Infectious Diseases, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
| | - Yu Chen
- Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Morante M, Pandiella A, Crespo P, Herrero A. Immune Checkpoint Inhibitors and RAS-ERK Pathway-Targeted Drugs as Combined Therapy for the Treatment of Melanoma. Biomolecules 2022; 12:1562. [PMID: 36358912 PMCID: PMC9687808 DOI: 10.3390/biom12111562] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/13/2022] [Accepted: 10/20/2022] [Indexed: 08/08/2023] Open
Abstract
Metastatic melanoma is a highly immunogenic tumor with very poor survival rates due to immune system escape-mechanisms. Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and the programmed death-1 (PD1) receptors, are being used to impede immune evasion. This immunotherapy entails an increment in the overall survival rates. However, melanoma cells respond with evasive molecular mechanisms. ERK cascade inhibitors are also used in metastatic melanoma treatment, with the RAF activity blockade being the main therapeutic approach for such purpose, and in combination with MEK inhibitors improves many parameters of clinical efficacy. Despite their efficacy in inhibiting ERK signaling, the rewiring of the melanoma cell-signaling results in disease relapse, constituting the reinstatement of ERK activation, which is a common cause of some resistance mechanisms. Recent studies revealed that the combination of RAS-ERK pathway inhibitors and ICI therapy present promising advantages for metastatic melanoma treatment. Here, we present a recompilation of the combined therapies clinically evaluated in patients.
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Affiliation(s)
- Marta Morante
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad de Cantabria, 39011 Santander, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28009 Madrid, Spain
| | - Atanasio Pandiella
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28009 Madrid, Spain
- Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)—Universidad de Salamanca and IBSAL, 37007 Salamanca, Spain
| | - Piero Crespo
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad de Cantabria, 39011 Santander, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28009 Madrid, Spain
| | - Ana Herrero
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad de Cantabria, 39011 Santander, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28009 Madrid, Spain
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10
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Song Y, Huang J, Wang K, Li Y. To Identify Adenomatous Polyposis Coli Gene Mutation as a Predictive Marker of Endometrial Cancer Immunotherapy. Front Cell Dev Biol 2022; 10:935650. [PMID: 35938175 PMCID: PMC9354690 DOI: 10.3389/fcell.2022.935650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/17/2022] [Indexed: 11/16/2022] Open
Abstract
The adenomatous polyposis coli (APC) gene is the chromatin-remodeling-related gene and a typical tumor suppressor. Patients with a high expression of programmed death-ligand 1 (PD-L1) or a high level of tumor mutational burden (TMB) may benefit from immunotherapy in endometrial cancer (EC). This study aimed to demonstrate the role of APC in the diagnosis and immunotherapy treatment of EC. We performed an integrative analysis of a commercial panel including 520 cancer-related genes on 99 tumors from an endometrial cancer cohort in China and DNA-seq data from The Cancer Genome Atlas (TCGA) to identify new gene mutations as endometrial cancer immunotherapy markers. We found that the significant mutant genes that correlated with the PD-L1 expression and TMB were related to the chromatin state and generated a discovery set having 12 mutated genes, including the APC gene, which was identified as a new marker for immunotherapy. Further analysis revealed that tumors with the APC mutation had high TMB, increased expression of PD-L1, and increased lymphocytic infiltration. Next, we verified that APC has an inactive mutation in EC, which may affect the immune response, including PD-L1 expression, microsatellite instability, and lymphocytic infiltrate. Furthermore, patients with the APC mutation had longer overall survival. Our study demonstrates that APC could play an important role in enhancing the response to endometrial cancer treatment, particularly immunotherapy.
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Affiliation(s)
- Yunfeng Song
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jian Huang
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kai Wang
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
- *Correspondence: Kai Wang, ; Yiran Li,
| | - Yiran Li
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
- Harvard Medical School, Boston, MA, United States
- *Correspondence: Kai Wang, ; Yiran Li,
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11
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Luo HY, Shen HY, Perkins RS, Wang YX. Adenosine Kinase on Deoxyribonucleic Acid Methylation: Adenosine Receptor-Independent Pathway in Cancer Therapy. Front Pharmacol 2022; 13:908882. [PMID: 35721189 PMCID: PMC9200284 DOI: 10.3389/fphar.2022.908882] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/16/2022] [Indexed: 11/24/2022] Open
Abstract
Methylation is an important mechanism contributing to cancer pathology. Methylation of tumor suppressor genes and oncogenes has been closely associated with tumor occurrence and development. New insights regarding the potential role of the adenosine receptor-independent pathway in the epigenetic modulation of DNA methylation offer the possibility of new interventional strategies for cancer therapy. Targeting DNA methylation of cancer-related genes is a promising therapeutic strategy; drugs like 5-Aza-2′-deoxycytidine (5-AZA-CdR, decitabine) effectively reverse DNA methylation and cancer cell growth. However, current anti-methylation (or methylation modifiers) are associated with severe side effects; thus, there is an urgent need for safer and more specific inhibitors of DNA methylation (or DNA methylation modifiers). The adenosine signaling pathway is reported to be involved in cancer pathology and participates in the development of tumors by altering DNA methylation. Most recently, an adenosine metabolic clearance enzyme, adenosine kinase (ADK), has been shown to influence methylation on tumor suppressor genes and tumor development and progression. This review article focuses on recent updates on ADK and its two isoforms, and its actions in adenosine receptor-independent pathways, including methylation modification and epigenetic changes in cancer pathology.
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Affiliation(s)
- Hao-Yun Luo
- Chongqing Medical University, Chongqing, China.,Department of Gastrointestinal and Anorectal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Hai-Ying Shen
- Department of Neuroscience, Legacy Research Institute, Portland, OR, United States.,Integrative Physiology and Neuroscience, Washington State University, Vancouver, WA, United States
| | - R Serene Perkins
- Legacy Tumor Bank, Legacy Research Institute, Portland, OR, United States.,Mid-Columbia Medical Center, The Dalles, OR, United States
| | - Ya-Xu Wang
- Chongqing Medical University, Chongqing, China.,Department of Gastrointestinal and Anorectal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
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12
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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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13
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Karin M, Shalapour S. Regulation of antitumor immunity by inflammation-induced epigenetic alterations. Cell Mol Immunol 2022; 19:59-66. [PMID: 34465885 PMCID: PMC8752743 DOI: 10.1038/s41423-021-00756-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 08/02/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammation promotes tumor development, progression, and metastatic dissemination and causes treatment resistance. The accumulation of genetic alterations and loss of normal cellular regulatory processes are not only associated with cancer growth and progression but also result in the expression of tumor-specific and tumor-associated antigens that may activate antitumor immunity. This antagonism between inflammation and immunity and the ability of cancer cells to avoid immune detection affect the course of cancer development and treatment outcomes. While inflammation, particularly acute inflammation, supports T-cell priming, activation, and infiltration into infected tissues, chronic inflammation is mostly immunosuppressive. However, the main mechanisms that dictate the outcome of the inflammation-immunity interplay are not well understood. Recent data suggest that inflammation triggers epigenetic alterations in cancer cells and components of the tumor microenvironment. These alterations can affect and modulate numerous aspects of cancer development, including tumor growth, the metabolic state, metastatic spread, immune escape, and immunosuppressive or immunosupportive leukocyte generation. In this review, we discuss the role of inflammation in initiating epigenetic alterations in immune cells, cancer-associated fibroblasts, and cancer cells and suggest how and when epigenetic interventions can be combined with immunotherapies to improve therapeutic outcomes.
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Affiliation(s)
- Michael Karin
- Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Shabnam Shalapour
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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14
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Kishi M, Asgarova A, Desterke C, Chaker D, Artus J, Turhan AG, Bennaceur-Griscelli A, Griscelli F. Evidence of Antitumor and Antimetastatic Potential of Induced Pluripotent Stem Cell-Based Vaccines in Cancer Immunotherapy. Front Med (Lausanne) 2021; 8:729018. [PMID: 34957134 PMCID: PMC8702815 DOI: 10.3389/fmed.2021.729018] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 11/18/2021] [Indexed: 12/27/2022] Open
Abstract
Cancer is maintained by the activity of a rare population of self-renewing "cancer stem cells" (CSCs), which are resistant to conventional therapies. CSCs over-express several proteins shared with induced pluripotent stem cells (iPSCs). We show here that allogenic or autologous murine iPSCs, combined with a histone deacetylase inhibitor (HDACi), are able to elicit major anti-tumor responses in a highly aggressive triple-negative breast cancer, as a relevant cancer stemness model. This immunotherapy strategy was effective in preventing tumor establishment and efficiently targeted CSCs by inducing extensive modifications of the tumor microenvironment. The anti-tumoral effect was correlated with the generation of CD4+, CD8+ T cells, and CD44+ CD62L- CCR7low CD127low T-effector memory cells, and the reduction of CD4+ CD25+FoxP3+ Tregs, Arg1+ CD11b+ Gr1+, and Arg1+ and CD11b+ Ly6+ myeloid-derived suppressor cell populations within the tumor. The anti-tumoral effect was associated with a reduction in metastatic dissemination and an improvement in the survival rate. These results demonstrate for the first time the clinical relevance of using an off-the-shelf allogeneic iPSC-based vaccine combined with an HDACi as a novel pan-cancer anti-cancer immunotherapy strategy against aggressive tumors harboring stemness features with high metastatic potential.
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Affiliation(s)
- Masae Kishi
- Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France
| | - Afag Asgarova
- Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France
| | - Christophe Desterke
- Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France.,Université Paris-Saclay, Faculté de Médecine, Kremlin Bicêtre, France
| | - Diana Chaker
- Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France
| | - Jérôme Artus
- Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France.,Université Paris-Saclay, Faculté de Médecine, Kremlin Bicêtre, France
| | - Ali G Turhan
- Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France.,Université Paris-Saclay, Faculté de Médecine, Kremlin Bicêtre, France.,APHP Paris-Saclay Service d'Hématologie, Hôpital Universitaire Paris Sud (AP-HP), Kremlin Bicêtre, France
| | - Annelise Bennaceur-Griscelli
- Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France.,Université Paris-Saclay, Faculté de Médecine, Kremlin Bicêtre, France.,APHP Paris-Saclay Service d'Hématologie, Hôpital Universitaire Paris Sud (AP-HP), Kremlin Bicêtre, France
| | - Frank Griscelli
- Institut National de la Santé et de la Recherche Médicale (INSERM) UA9-Human Pluripotent Stem Cell Core Facility, CITHERA Infrastructure-INGESTEM, Villejuif, France.,Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.,Département de Biologie Médicale et Pathologie Médicales, Gustave Roussy Cancer Campus, Villejuif, France
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15
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Zhao C, Liu Y, Ju S, Wang X. Pan-Cancer Analysis of the N6-Methyladenosine Eraser FTO as a Potential Prognostic and Immunological Biomarker. Int J Gen Med 2021; 14:7411-7422. [PMID: 34744452 PMCID: PMC8565892 DOI: 10.2147/ijgm.s331752] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 09/10/2021] [Indexed: 12/11/2022] Open
Abstract
Background Fat mass and obesity-associated protein (FTO) is a critical N6-methyladenosine (m6A) demethylase that participates in tumorigenesis and is associated with the prognosis of patients in some cancers. However, the key roles of FTO in pan-cancer are still largely obscure. Methods FTO expression levels in pan-cancer were estimated via the Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), and The Cancer Genome Atlas (TCGA) databases. Univariate survival analysis was used to estimate the effects of FTO on prognosis. In addition, we used the Tumor Immune Evaluation Resource (TIMER) to assess the immune cell infiltration of FTO gene across cancers. The association of FTO expression with immune checkpoint genes expression, DNA mismatch repair (MMR) gene mutation, DNA methyltransferases, microsatellite instability (MSI), and tumor mutational burden (TMB) was investigated using Spearman’s correlation analysis. Moreover, Gene Set Enrichment Analysis (GSEA) was utilized to identify critical pathways in cancers. The STRING website was used to reveal the protein–protein interaction (PPI) network of FTO. Results FTO was aberrantly expressed across cancers and survival analysis demonstrated that its expression was associated with clinical prognosis of many cancer patients. Specifically, FTO expression was significantly associated with immune infiltrating cells in colon adenocarcinoma, kidney renal clear cell carcinoma, and liver hepatocellular carcinoma. In addition, FTO expression was significantly associated with immune checkpoint genes expression, MMR, DNA methyltransferases levels, TMB, and MSI in multiple cancers. Moreover, the GSEA unveiled that FTO was involved in the regulation of tumors and immune-related signaling pathways. In addition, several m6A related genes were implicated in the PPI network of FTO. Conclusion FTO was related to patients’ prognosis and tumor immune infiltrates in various cancers, and may serve as a novel and potential prognostic and immune biomarker in human pan-cancer.
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Affiliation(s)
- Chengwen Zhao
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Yonghui Liu
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Shaoqing Ju
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China.,Department of Public Health, Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Xudong Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China.,Department of Public Health, Nantong University, Nantong, Jiangsu, People's Republic of China
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16
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Sanceau J, Gougelet A. Epigenetic mechanisms of liver tumor resistance to immunotherapy. World J Hepatol 2021; 13:979-1002. [PMID: 34630870 PMCID: PMC8473495 DOI: 10.4254/wjh.v13.i9.979] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/04/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver tumor, which stands fourth in rank of cancer-related deaths worldwide. The incidence of HCC is constantly increasing in correlation with the epidemic in diabetes and obesity, arguing for an urgent need for new treatments for this lethal cancer refractory to conventional treatments. HCC is the paradigm of inflammation-associated cancer, since more than 80% of HCC emerge consecutively to cirrhosis associated with a vast remodeling of liver microenvironment. In the recent decade, immunomodulatory drugs have been developed and have given impressive results in melanoma and later in several other cancers. In the present review, we will discuss the recent advancements concerning the use of immunotherapies in HCC, in particular those targeting immune checkpoints, used alone or in combination with other anti-cancers agents. We will address why these drugs demonstrate unsatisfactory results in a high proportion of liver cancers and the mechanisms of resistance developed by HCC to evade immune response with a focus on the epigenetic-related mechanisms.
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Affiliation(s)
- Julie Sanceau
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris 75006, France
| | - Angélique Gougelet
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris 75006, France.
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17
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Dhar R, Seethy A, Singh S, Pethusamy K, Srivastava T, Talukdar J, Rath GK, Karmakar S. Cancer immunotherapy: Recent advances and challenges. J Cancer Res Ther 2021; 17:834-844. [PMID: 34528529 DOI: 10.4103/jcrt.jcrt_1241_20] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Immunotherapy is a treatment that uses specific components of a person's immune system to fight diseases. This is usually done by stimulating or assisting one's immune system is attacking the offending agent - for instance, in the case of cancer - the target of immunotherapy will be cancer cells. Some types of immunotherapy are also called biologic therapy or biotherapy. One of the fundamental challenges that a living cell encounters are to accurately copy its genetic material to daughter cells during every single cell cycle. When this process goes haywire, genomic instability ensues, and genetic alterations ranging from nucleotide changes to chromosomal translocations and aneuploidy occur. Genomic instability arising out of DNA structural changes (indels, rearrangements, etc.,) can give rise to mutations predisposing to cancer. Cancer prevention refers to actions taken to mitigate the risk of getting cancer. The past decade has encountered an explosive rate of development of anticancer therapy ranging from standard chemotherapy to novel targeted small molecules that are nearly cancer specific, thereby reducing collateral damage. However, a new class of emerging therapy aims to train the body's defense system to fight against cancer. Termed as "cancer immunotherapy" is the new approach that has gained worldwide acceptance. It includes using antibodies that bind to and inhibit the function of proteins expressed by cancer cells or engineering and boosting the person's own T lymphocytes to target cancer. In this review, we summarized the recent advances and developments in cancer immunotherapy along with their shortcoming and challenges.
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Affiliation(s)
- Ruby Dhar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Ashikh Seethy
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi; Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, India
| | - Sunil Singh
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Karthikeyan Pethusamy
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Tryambak Srivastava
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Joyeeta Talukdar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Goura Kishor Rath
- Department of Radiation Oncology, DRBRAIRCH, All India Institute of Medical Sciences, New Delhi; Department of Radiation Oncology, NCI, All India Institute of Medical Sciences, Jhajjar, Haryana, India
| | - Subhradip Karmakar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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18
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Chen Y, Xia F, Jiang B, Wang W, Li X. Role of Immune Cell-Specific Hypermethylation Signatures in Classification and Risk Stratification of Breast Cancer. Front Med (Lausanne) 2021; 8:674338. [PMID: 34513864 PMCID: PMC8426625 DOI: 10.3389/fmed.2021.674338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 08/06/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Epigenetic regulation, including DNA methylation, plays a major role in shaping the identity and function of immune cells. Innate and adaptive immune cells recruited into tumor tissues contribute to the formation of the tumor immune microenvironment (TIME), which is closely involved in tumor progression in breast cancer (BC). However, the specific methylation signatures of immune cells have not been thoroughly investigated yet. Additionally, it remains unknown whether immune cells-specific methylation signatures can identify subgroups and stratify the prognosis of BC patients. Methods: DNA methylation profiles of six immune cell types from eight datasets downloaded from the Gene Expression Omnibus were collected to identify immune cell-specific hypermethylation signatures (IC-SHMSs). Univariate and multivariate cox regression analyses were performed using BC data obtained from The Cancer Genome Atlas to identify the prognostic value of these IC-SHMSs. An unsupervised clustering analysis of the IC-SHMSs with prognostic value was performed to categorize BC patients into subgroups. Multiple Cox proportional hazard models were constructed to explore the role of IC-SHMSs and their relationship to clinical characteristics in the risk stratification of BC patients. Integrated discrimination improvement (IDI) was performed to determine whether the improvement of IC-SHMSs on clinical characteristics in risk stratification was statistically significant. Results: A total of 655 IC-SHMSs of six immune cell types were identified. Thirty of them had prognostic value, and 10 showed independent prognostic value. Four subgroups of BC patients, which showed significant heterogeneity in terms of survival prognosis and immune landscape, were identified. The model incorporating nine IC-SHMSs showed similar survival prediction accuracy as the clinical model incorporating age and TNM stage [3-year area under the curve (AUC): 0.793 vs. 0.785; 5-year AUC: 0.735 vs. 0.761]. Adding the IC-SHMSs to the clinical model significantly improved its prediction accuracy in risk stratification (3-year AUC: 0.897; 5-year AUC: 0.856). The results of IDI validated the statistical significance of the improvement (p < 0.05). Conclusions: Our study suggests that IC-SHMSs may serve as signatures of classification and risk stratification in BC. Our findings provide new insights into epigenetic signatures, which may help improve subgroup identification, risk stratification, and treatment management.
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Affiliation(s)
- Yong Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Fada Xia
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Bo Jiang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Wenlong Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xinying Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
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19
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Mokhtari RB, Sambi M, Qorri B, Baluch N, Ashayeri N, Kumar S, Cheng HLM, Yeger H, Das B, Szewczuk MR. The Next-Generation of Combination Cancer Immunotherapy: Epigenetic Immunomodulators Transmogrify Immune Training to Enhance Immunotherapy. Cancers (Basel) 2021; 13:3596. [PMID: 34298809 PMCID: PMC8305317 DOI: 10.3390/cancers13143596] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer immunotherapy harnesses the immune system by targeting tumor cells that express antigens recognized by immune system cells, thus leading to tumor rejection. These tumor-associated antigens include tumor-specific shared antigens, differentiation antigens, protein products of mutated genes and rearrangements unique to tumor cells, overexpressed tissue-specific antigens, and exogenous viral proteins. However, the development of effective therapeutic approaches has proven difficult, mainly because these tumor antigens are shielded, and cells primarily express self-derived antigens. Despite innovative and notable advances in immunotherapy, challenges associated with variable patient response rates and efficacy on select tumors minimize the overall effectiveness of immunotherapy. Variations observed in response rates to immunotherapy are due to multiple factors, including adaptative resistance, competency, and a diversity of individual immune systems, including cancer stem cells in the tumor microenvironment, composition of the gut microbiota, and broad limitations of current immunotherapeutic approaches. New approaches are positioned to improve the immune response and increase the efficacy of immunotherapies, highlighting the challenges that the current global COVID-19 pandemic places on the present state of immunotherapy.
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Affiliation(s)
- Reza Bayat Mokhtari
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (M.S.); (B.Q.)
- Department of Experimental Therapeutics, Thoreau Laboratory for Global Health, M2D2, University of Massachusetts, Lowell, MA 01852, USA;
| | - Manpreet Sambi
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (M.S.); (B.Q.)
| | - Bessi Qorri
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (M.S.); (B.Q.)
| | - Narges Baluch
- Department of Immunology and Allergy, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada;
| | - Neda Ashayeri
- Division of Hematology & Oncology, Department of Pediatrics, Ali-Asghar Children Hospital, Iran University of Medical Science, Tehran 1449614535, Iran;
| | - Sushil Kumar
- QPS, Holdings LLC, Pencader Corporate Center, 110 Executive Drive, Newark, DE 19702, USA;
| | - Hai-Ling Margaret Cheng
- The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5G 1M1, Canada;
- Translational Biology & Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
| | - Herman Yeger
- Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada;
| | - Bikul Das
- Department of Experimental Therapeutics, Thoreau Laboratory for Global Health, M2D2, University of Massachusetts, Lowell, MA 01852, USA;
- KaviKrishna Laboratory, Department of Cancer and Stem Cell Biology, GBP, Indian Institute of Technology, Guwahati 781039, India
| | - Myron R. Szewczuk
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (M.S.); (B.Q.)
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20
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Hu P, Sun M, Lu F, Wang S, Hou L, Yu Y, Zhang Y, Sun L, Yao J, Yang F, Wang C, Ma Z. Polymerized vorinostat mediated photodynamic therapy using lysosomal spatiotemporal synchronized drug release complex. Colloids Surf B Biointerfaces 2021; 205:111903. [PMID: 34144323 DOI: 10.1016/j.colsurfb.2021.111903] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/01/2021] [Accepted: 06/03/2021] [Indexed: 01/16/2023]
Abstract
A combination of photodynamic therapy (PDT) and histone deacetylase inhibitor (HDACis) could potentiate single-mode anti-tumor activity of HDACis or PDT to inhibit tumor relapse and metastasis. However, poor solubility and heterogeneity in cellular uptake and tissue distribution hamper the dual mode antitumor effect. For a controlled drug release of photosensitizers and HDACis in cytoplasm, photosensitizer pyropheophorbide-a (Pyro) encapsulated in polymer polyethylene glycol-b-poly (asparaginyl-vorinostat) (simplified as Pyro@FPPS) are fabricated to achieve their lysosomal spatiotemporal synchronized release. With HDACis modeling PDT in vitro and in vivo, it seems that polymerized Vorinostat encapsulated photosensitizers significantly inhibited the tumor proliferation and metastasis by spatiotemporal synchronized drugs release, and Pyro@FPPS reported here reveals a promising prospect to exert drugs' synergistic effect in a spatiotemporal synchronized manner and can be an effective strategy to inhibit tumor growth, recurrence and metastasis in clinic.
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Affiliation(s)
- Pengwei Hu
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; Harbin Institute of Technology (Shenzhen), School of Science, Shenzhen, People's Republic of China; Department of Pharmacy, Hebei North University, Zhangjiakou, People's Republic of China
| | - Miao Sun
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Fengkun Lu
- Department of Pharmacy, Hebei North University, Zhangjiakou, People's Republic of China
| | - Sizhen Wang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Lei Hou
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; Department of Pharmacy, Hebei North University, Zhangjiakou, People's Republic of China
| | - Yingjie Yu
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Yunchang Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Linhong Sun
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Jianzhong Yao
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Feng Yang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
| | - Chen Wang
- Department of Oncology, Ruijin North Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
| | - Zhiqiang Ma
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
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21
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Lu F, Hou L, Wang S, Yu Y, Zhang Y, Sun L, Wang C, Ma Z, Yang F. Lysosome activable polymeric vorinostat encapsulating PD-L1KD for a combination of HDACi and immunotherapy. Drug Deliv 2021; 28:963-972. [PMID: 34036867 PMCID: PMC8158275 DOI: 10.1080/10717544.2021.1927246] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
PD-1/PD-L1 blocking therapy has become one of the most promising methods in the field of tumor treatment. However, it encounters the challenge of immune escape due to the exhaustion of T cells. Studies have shown that the epigenetic regulation drug histone deacetylase inhibitor (HDACi) may be able to reverse exhausted T cells by changing the epigenetic transcription program. Therefore, the combination of epigenetic therapy and PD-1/PD-L1 blockade therapy is expected to reverse the immune escape, whereas the overriding goal should aim at the spontaneous release and synergy of PD-1/PD-L1 blocking siRNA and HDACi. In this study, we develop PDDS{polyethylene glycol-b-asparaginate(diethylenetriamine-vorinostat), (PEG-b-P[Asp(DET-SAHA)n] PPDS)}encapsulating siRNA-PD-L1to provide micelles siRNA-PD-L1-loaded micelles (siRNA@PPDS). Transmission electron microscope (TEM) images demonstrate that siRNA@PPDS micelles presented spherical morphology with a size of about 120 nm; hydrodynamic data analysis indicates pH sensitivity of siRNA@PPDS micelles. The experiments reveal that siRNA@PPDS micelles could be well uptaken by the tumor cells to silence the expression of PD-L1 protein in a dose-dependent manner; compared with the free SAHA, the SAHA-loaded micelles PPDS show higher cytotoxicity to induce tumor cell apoptosis and block cell cycle in G1 phase on melanoma-bearing mice, siRNA@PPDS has shown outstanding inhibition of tumor growth and pulmonary metastasis. By comprehensively activating the immune system, lysosome activable polymeric vorinostat encapsulating PD-L1KD for the combination therapy of PD-L1-KD and HDACIs can be an effective strategy to reverse the unresponsiveness of immune checkpoint inhibitors and a promising treatment to inhibit tumor growth, recurrence, and metastasis in clinic.
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Affiliation(s)
- Fengkun Lu
- Department of Pharmacy, Hebei North University Hebei Key Laboratory of Neuropharmacology, Zhangjiakou, People's Republic of China
| | - Lei Hou
- Department of Pharmacy, Hebei North University Hebei Key Laboratory of Neuropharmacology, Zhangjiakou, People's Republic of China
| | - Sizhen Wang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Yingjie Yu
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Yunchang Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Linhong Sun
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Chen Wang
- Department of Oncology, Ruijin North Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Zhiqiang Ma
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Feng Yang
- Department of Pharmacy, Hebei North University Hebei Key Laboratory of Neuropharmacology, Zhangjiakou, People's Republic of China.,School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
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22
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Liu ZL, Liu JH, Staiculescu D, Chen J. Combination of molecularly targeted therapies and immune checkpoint inhibitors in the new era of unresectable hepatocellular carcinoma treatment. Ther Adv Med Oncol 2021; 13:17588359211018026. [PMID: 34104226 PMCID: PMC8150670 DOI: 10.1177/17588359211018026] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Multikinase inhibitors (MKIs) have been the only first-line treatment for advanced hepatocellular carcinoma (HCC) for more than a decade, until the approval of immune checkpoint inhibitors (ICIs). Moreover, the combination regimen of atezolizumab (anti-programmed cell death protein ligand 1 antibody) plus bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) has recently been demonstrated to have superior efficacy when compared with sorafenib monotherapy. The remarkable efficacy has made this combination therapy the new standard treatment for advanced HCC. In addition to MKIs, many other molecularly targeted therapies are under investigation, some of which have shown promising results. Therefore, in the era of immuno-oncology, there is a significant rationale for testing the combinations of molecularly targeted therapies and ICIs. Indeed, numerous preclinical and clinical studies have shown the synergic antitumor efficacy of such combinations. In this review, we aim to summarize the current knowledge on the combination of molecularly targeted therapies and immune checkpoint therapies for HCC from both preclinical and clinical perspectives.
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Affiliation(s)
- Ze-Long Liu
- Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jing-Hua Liu
- Department of Hepatobiliary Surgery and Professor Cai’s Laboratory, Linyi People’s Hospital, Linyi, Shandong Province, China
| | - Daniel Staiculescu
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jiang Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, No. 3, East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
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23
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Mehdi A, Rabbani SA. Role of Methylation in Pro- and Anti-Cancer Immunity. Cancers (Basel) 2021; 13:cancers13030545. [PMID: 33535484 PMCID: PMC7867049 DOI: 10.3390/cancers13030545] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/09/2021] [Accepted: 01/27/2021] [Indexed: 12/12/2022] Open
Abstract
DNA and RNA methylation play a vital role in the transcriptional regulation of various cell types including the differentiation and function of immune cells involved in pro- and anti-cancer immunity. Interactions of tumor and immune cells in the tumor microenvironment (TME) are complex. TME shapes the fate of tumors by modulating the dynamic DNA (and RNA) methylation patterns of these immune cells to alter their differentiation into pro-cancer (e.g., regulatory T cells) or anti-cancer (e.g., CD8+ T cells) cell types. This review considers the role of DNA and RNA methylation in myeloid and lymphoid cells in the activation, differentiation, and function that control the innate and adaptive immune responses in cancer and non-cancer contexts. Understanding the complex transcriptional regulation modulating differentiation and function of immune cells can help identify and validate therapeutic targets aimed at targeting DNA and RNA methylation to reduce cancer-associated morbidity and mortality.
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Affiliation(s)
- Ali Mehdi
- Department of Human Genetics, McGill University, Montreal, QC H3A 2B4, Canada;
- Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Shafaat A. Rabbani
- Department of Human Genetics, McGill University, Montreal, QC H3A 2B4, Canada;
- Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
- Correspondence: ; Tel.: +1-514-843-1632
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24
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Peng M, Xiao D, Bu Y, Long J, Yang X, Lv S, Yang X. Novel Combination Therapies for the Treatment of Bladder Cancer. Front Oncol 2021; 10:539527. [PMID: 33585182 PMCID: PMC7873600 DOI: 10.3389/fonc.2020.539527] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 12/07/2020] [Indexed: 12/29/2022] Open
Abstract
Bladder cancer is the ninth most frequently diagnosed cancer world-wide and ranks 13th in cancer-related deaths. Two tremendous breakthroughs in bladder cancer therapy over the last decades are the approval of immune checkpoint inhibitors(ICIs)and the fibroblast growth factor receptor tyrosine kinase inhibitor (FGFR-TKI) erdafitinib for treating this deadly disease. Despite the beneficial effects of these approaches, the low response rate and the potential resistance of the cancer are major concerns. Hence, novel combination therapies to overcome these limitations have been investigated. In this context, combining immunotherapy with targeted drugs is an appealing therapeutic option to improve response and reduce the emergence of resistance in the management of bladder cancer. In this review, the rationale of using different therapeutic combinations is discussed according to the mechanistic differences, emphasizing the efficacy and safety based on evidence collected from preclinical and clinical studies. Finally, we highlight the limitations of these combinations and provide suggestions for further efforts in this challenging field.
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Affiliation(s)
- Mei Peng
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, China
| | - Di Xiao
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, China
| | - Yizhi Bu
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, China
| | - Jiahui Long
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, China
| | - Xue Yang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
| | - Shuhe Lv
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoping Yang
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, China
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25
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Natoli M, Gallon J, Lu H, Amgheib A, Pinato DJ, Mauri FA, Marafioti T, Akarca AU, Ullmo I, Ip J, Aboagye EO, Brown R, Karadimitris A, Ghaem-Maghami S. Transcriptional analysis of multiple ovarian cancer cohorts reveals prognostic and immunomodulatory consequences of ERV expression. J Immunother Cancer 2021; 9:jitc-2020-001519. [PMID: 33436485 PMCID: PMC7805370 DOI: 10.1136/jitc-2020-001519] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Endogenous retroviruses (ERVs) play a role in a variety of biological processes, including embryogenesis and cancer. DNA methyltransferase inhibitors (DNMTi)-induced ERV expression triggers interferon responses in ovarian cancer cells via the viral sensing machinery. Baseline expression of ERVs also occurs in cancer cells, though this process is poorly understood and previously unexplored in epithelial ovarian cancer (EOC). Here, the prognostic and immunomodulatory consequences of baseline ERV expression was assessed in EOC. METHODS ERV expression was assessed using EOC transcriptional data from The Cancer Genome Atlas (TCGA) and from an independent cohort (Hammersmith Hospital, HH), as well as from untreated or DNMTi-treated EOC cell lines. Least absolute shrinkage and selection operator (LASSO) logistic regression defined an ERV expression score to predict patient prognosis. Immunohistochemistry (IHC) was conducted on the HH cohort. Combination of DNMTi treatment with γδ T cells was tested in vitro, using EOC cell lines and patient-derived tumor cells. RESULTS ERV expression was found to define clinically relevant subsets of EOC patients. An ERV prognostic score was successfully generated in TCGA and validated in the independent cohort. In EOC patients from this cohort, a high ERV score was associated with better survival (log-rank p=0.0009) and correlated with infiltration of CD8+PD1+T cells (r=0.46, p=0.0001). In the TCGA dataset, a higher ERV score was found in BRCA1/2 mutant tumors, compared to wild type (p=0.015), while a lower ERV score was found in CCNE1 amplified tumors, compared to wild type (p=0.019). In vitro, baseline ERV expression dictates the level of ERV induction in response to DNMTi. Manipulation of an ERV expression threshold by DNMTi resulted in improved EOC cell killing by cytotoxic immune cells. CONCLUSIONS These findings uncover the potential for baseline ERV expression to robustly inform EOC patient prognosis, influence tumor immune infiltration and affect antitumor immunity.
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Affiliation(s)
- Marina Natoli
- Department of Surgery and Cancer, Imperial College London, London, UK.,Department of Biomedicine, University Hospital Basel, Basel, Switzerland
| | - John Gallon
- Department of Surgery and Cancer, Imperial College London, London, UK.,Department of Biomedicine, University Hospital Basel, Basel, Switzerland
| | - Haonan Lu
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Ala Amgheib
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - David J Pinato
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Francesco A Mauri
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Teresa Marafioti
- Department of Pathology, University College London Cancer Institute, London, UK
| | - Ayse U Akarca
- Department of Pathology, University College London Cancer Institute, London, UK
| | - Ines Ullmo
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Jacey Ip
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Eric O Aboagye
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Robert Brown
- Department of Surgery and Cancer, Imperial College London, London, UK.,Department of Pathology, Institute of Cancer Research, London, UK
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26
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Wang Z, Wu X. Study and analysis of antitumor resistance mechanism of PD1/PD-L1 immune checkpoint blocker. Cancer Med 2020; 9:8086-8121. [PMID: 32875727 PMCID: PMC7643687 DOI: 10.1002/cam4.3410] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/04/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022] Open
Abstract
Immunocheckpoint proteins of tumor infiltrating lymphocytes play an important role in tumor prognosis in the course of tumor clinicopathology. PD‐1 (Programmed cell death protein 1) is an important immunosuppressive molecule. By binding to PD‐L1 (programmed cell death‐ligand 1), it blocks TCR and its costimulus signal transduction, inhibits the activation and proliferation of T cells, depletes the function of effector T cells, and enables tumor cells to achieve immune escape. In recent years, immunocheckpoint blocking therapy targeting the PD‐1/PD‐L1 axis has achieved good results in a variety of malignant tumors, pushing tumor immunotherapy to a new milestone, such as anti‐PD‐1 monoclonal antibody Nivolumab, Pembrolizumab, and anti‐PD‐L1 monoclonal antibody Atezolizumab, which are considered as potential antitumor drugs. It was found in clinical use that some patients obtained long‐term efficacy, but most of them developed drug resistance recurrence in the later stage. The high incidence of drug resistance (including primary and acquired drug resistance) still cannot be ignored, which limited its clinical application and became a new problem in this field. Due to tumor heterogeneity, current limited research shows that PD‐1 or PD‐L1 monoclonal antibody drug resistance may be related to the following factors: mutation of tumor antigen and antigen presentation process, multiple immune checkpoint interactions, immune microenvironment changes dynamically, activation of oncogenic pathways, gene mutation and epigenetic changes of key proteins in tumors, tumor competitive metabolism, and accumulation of metabolites, etc, mechanisms of resistance are complex. Therefore, it is the most urgent task to further elucidate the mechanism of immune checkpoint inhibitor resistance, discover multitumor universal biomarkers, and develop new target agents to improve the response rate of immunotherapy in patients. In this study, the mechanism of anti‐PD‐1/PD‐L1 drug resistance in tumors, the potential biomarkers for predicting PD‐1 acquired resistance, and the recent development of combination therapy were reviewed one by one. It is believed that, based on the complex mechanism of drug resistance, it is of no clinical significance to simply search for and regulate drug resistance targets, and it may even produce drug resistance again soon. It is speculated that according to the possible tumor characteristics, three types of treatment methods should be combined to change the tumor microenvironment ecology and eliminate various heterogeneous tumor subsets, so as to reduce tumor drug resistance and improve long‐term clinical efficacy.
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Affiliation(s)
- Zhengyi Wang
- GCP Center of Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital Medical Sciences, Chengdu City, Sichuan Province, China.,Institute of Laboratory Animals of Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu City, Sichuan Province, China
| | - Xiaoying Wu
- Ministry of Education and Training, Second People's Hospital, Chengdu City, Sichuan Province, China
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27
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Guo C, Wang Q, Zhang X, Lu F, Sun M, Zeng P, Sun L, She L, Wang B, Zhang Y, Wang C, Ma Z, Yang F. Gelated Vorinostat with inner-lysosome triggered release for tumor-targeting chemotherapy. Colloids Surf B Biointerfaces 2020; 194:111144. [PMID: 32535244 DOI: 10.1016/j.colsurfb.2020.111144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/13/2020] [Accepted: 05/16/2020] [Indexed: 12/16/2022]
Abstract
Histonedeacetylase inhibitor (HDACi) has great potential in targeted antitumor therapy by inhibiting tumor migration, invasion, and metastasis. As one of the typical HDACis, vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) was approved as a therapeutic agent for cancer therapy, however, challenges remain due to their poor solubility, short half-life and low efficiency in cellular penetration. Considering the disadvantages of usual drug carriers, folate and vorinostat bound BSA nanogel (FVBN)was fabricated to implement higher solubility, stability, cellular uptake, and lipase-responsive release. With good dispersion and stability, FVBN significantly increased the cellular uptake of vorinostat through folate-mediated endocytosis. FVBN exhibited comparable cytotoxicity with free SAHA, and the growth of tumor cells was blocked in G1/G0 phase just like SAHA performed in cell cycle arrest tests. Moreover, FVBN not only effectively inhibited the growth of melanoma but also observably prevented pulmonary metastasis of melanoma. In the experiment against nude mice bearing solid ovarian cancer, FVBN showed excellent antitumor effect without liver damage, demonstrating the superiority of gelated and inner-lysosome triggered release strategies to the free SAHA, and it is promising to expand the scope of application of HDACi in clinical cancer therapy.
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Affiliation(s)
- Changyong Guo
- Department of Pharmacy, Hebei North University Hebei Key Laboratory of Neuropharmacology, Zhangjiakou, People's Republic of China
| | - Qirong Wang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Xingjie Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Fengkun Lu
- Department of Pharmacy, Hebei North University Hebei Key Laboratory of Neuropharmacology, Zhangjiakou, People's Republic of China; School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Miao Sun
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Peiyu Zeng
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Linhong Sun
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Lan She
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Bingkai Wang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Yunchang Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China
| | - Chen Wang
- Department of Oncology, Ruijin North Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
| | - Zhiqiang Ma
- School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
| | - Feng Yang
- Department of Pharmacy, Hebei North University Hebei Key Laboratory of Neuropharmacology, Zhangjiakou, People's Republic of China; School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
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28
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Idrissou M, Sanchez A, Penault-Llorca F, Bignon YJ, Bernard-Gallon D. Epi-drugs as triple-negative breast cancer treatment. Epigenomics 2020; 12:725-742. [PMID: 32396394 DOI: 10.2217/epi-2019-0312] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Triple-negative breast cancer (TNBC) types with poor prognosis are due to the absence of estrogen receptors, progesterone receptors and HEGFR-2. The lack of suitable therapy for TNBC has led the research community to turn toward epigenetic regulation and its protagonists that can modulate certain oncogenes and tumor suppressors. This has opened an important new field of therapy using epi-drugs, in preclinical and clinical trials. The epi-drugs are natural or synthetic molecules capable of inhibiting or modulating the activity of epigenetic proteins such as DNA methyltransferases, modulating the expression of interferon microRNAs, as well as histone methyltransferases, demethylases, acetyltransferases and deacetylases. This review investigated the epi-drugs used in the treatment of TNBC.
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Affiliation(s)
- Mouhamed Idrissou
- Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 place Henri-Dunant, Clermont-Ferrand 63001, France.,INSERM U 1240 Molecular Imagery & Theranostic Strategies (IMoST), 58 Rue Montalembert, Clermont-Ferrand 63005, France
| | - Anna Sanchez
- Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 place Henri-Dunant, Clermont-Ferrand 63001, France.,INSERM U 1240 Molecular Imagery & Theranostic Strategies (IMoST), 58 Rue Montalembert, Clermont-Ferrand 63005, France
| | - Frédérique Penault-Llorca
- INSERM U 1240 Molecular Imagery & Theranostic Strategies (IMoST), 58 Rue Montalembert, Clermont-Ferrand 63005, France.,Department of Biopathology, Centre Jean Perrin, 58 Rue Montalembert, Clermont-Ferrand 63011, France
| | - Yves-Jean Bignon
- Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 place Henri-Dunant, Clermont-Ferrand 63001, France.,INSERM U 1240 Molecular Imagery & Theranostic Strategies (IMoST), 58 Rue Montalembert, Clermont-Ferrand 63005, France
| | - Dominique Bernard-Gallon
- Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 place Henri-Dunant, Clermont-Ferrand 63001, France.,INSERM U 1240 Molecular Imagery & Theranostic Strategies (IMoST), 58 Rue Montalembert, Clermont-Ferrand 63005, France
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29
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Maryamchik E, Gallagher KME, Preffer FI, Kadauke S, Maus MV. New directions in chimeric antigen receptor T cell [CAR-T] therapy and related flow cytometry. CYTOMETRY PART B-CLINICAL CYTOMETRY 2020; 98:299-327. [PMID: 32352629 DOI: 10.1002/cyto.b.21880] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/01/2020] [Accepted: 04/07/2020] [Indexed: 12/12/2022]
Abstract
Chimeric antigen receptor (CAR) T cells provide a promising approach to the treatment of hematologic malignancies and solid tumors. Flow cytometry is a powerful analytical modality, which plays an expanding role in all stages of CAR T therapy, from lymphocyte collection, to CAR T cell manufacturing, to in vivo monitoring of the infused cells and evaluation of their function in the tumor environment. Therefore, a thorough understanding of the new directions is important for designing and implementing CAR T-related flow cytometry assays in the clinical and investigational settings. However, the speed of new discoveries and the multitude of clinical and preclinical trials make it challenging to keep up to date in this complex field. In this review, we summarize the current state of CAR T therapy, highlight the areas of emergent research, discuss applications of flow cytometry in modern cell therapy, and touch upon several considerations particular to CAR detection and assessing the effectiveness of CAR T therapy.
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Affiliation(s)
- Elena Maryamchik
- Department of Pathology and Laboratory Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | | | - Frederic I Preffer
- Clinical Cytometry, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Stephan Kadauke
- Department of Pathology and Laboratory Medicine, Cell and Gene Therapy Laboratory, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Marcela V Maus
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Cellular Immunotherapy Program, Department of Medicine, Boston, Massachusetts, USA
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30
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Castagnoli L, De Santis F, Volpari T, Vernieri C, Tagliabue E, Di Nicola M, Pupa SM. Cancer Stem Cells: Devil or Savior-Looking behind the Scenes of Immunotherapy Failure. Cells 2020; 9:E555. [PMID: 32120774 PMCID: PMC7140486 DOI: 10.3390/cells9030555] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/19/2020] [Accepted: 02/21/2020] [Indexed: 12/12/2022] Open
Abstract
Although the introduction of immunotherapy has tremendously improved the prognosis of patients with metastatic cancers of different histological origins, some tumors fail to respond or develop resistance. Broadening the clinical efficacy of currently available immunotherapy strategies requires an improved understanding of the biological mechanisms underlying cancer immune escape. Globally, tumor cells evade immune attack using two main strategies: avoiding recognition by immune cells and instigating an immunosuppressive tumor microenvironment. Emerging data suggest that the clinical efficacy of chemotherapy or molecularly targeted therapy is related to the ability of these therapies to target cancer stem cells (CSCs). However, little is known about the role of CSCs in mediating tumor resistance to immunotherapy. Due to their immunomodulating features and plasticity, CSCs can be especially proficient at evading immune surveillance, thus potentially representing the most prominent malignant cell component implicated in primary or acquired resistance to immunotherapy. The identification of immunomodulatory properties of CSCs that include mechanisms that regulate their interactions with immune cells, such as bidirectional release of particular cytokines/chemokines, fusion of CSCs with fusogenic stromal cells, and cell-to-cell communication exerted by extracellular vesicles, may significantly improve the efficacy of current immunotherapy strategies. The purpose of this review is to discuss the current scientific evidence linking CSC biological, immunological, and epigenetic features to tumor resistance to immunotherapy.
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Affiliation(s)
- Lorenzo Castagnoli
- Department of Research, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Amadeo 42, 20133 Milan, Italy; (L.C.); (E.T.)
| | - Francesca De Santis
- Department of Medical Oncology and Hematology, Unit of Immunotherapy and Anticancer Innovative Therapeutics, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, 20133 Milan, Italy; (F.D.S.); (T.V.); (M.D.N.)
| | - Tatiana Volpari
- Department of Medical Oncology and Hematology, Unit of Immunotherapy and Anticancer Innovative Therapeutics, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, 20133 Milan, Italy; (F.D.S.); (T.V.); (M.D.N.)
| | - Claudio Vernieri
- Department of Medical Oncology and Hematology, FIRC Institute of Molecular Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy;
- IFOM, FIRC Institute of Molecular Oncology, via Adamello 16, 20139 Milan, Italy
| | - Elda Tagliabue
- Department of Research, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Amadeo 42, 20133 Milan, Italy; (L.C.); (E.T.)
| | - Massimo Di Nicola
- Department of Medical Oncology and Hematology, Unit of Immunotherapy and Anticancer Innovative Therapeutics, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Venezian 1, 20133 Milan, Italy; (F.D.S.); (T.V.); (M.D.N.)
| | - Serenella M. Pupa
- Department of Research, Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via Amadeo 42, 20133 Milan, Italy; (L.C.); (E.T.)
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Ceccarelli V, Ronchetti S, Marchetti MC, Calvitti M, Riccardi C, Grignani F, Vecchini A. Molecular mechanisms underlying eicosapentaenoic acid inhibition of HDAC1 and DNMT expression and activity in carcinoma cells. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2020; 1863:194481. [PMID: 31923609 DOI: 10.1016/j.bbagrm.2020.194481] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 12/30/2019] [Accepted: 01/05/2020] [Indexed: 12/20/2022]
Abstract
DNA methylation and histone acetylation, the most studied epigenetic changes, drive and maintain cancer phenotypes. DNA methyltransferase (DNMT) dysregulation promoted localized hypermethylation in CpG rich regions while upregulated histone deacetylases (HDAC) deacetylated histone tails. Both changes led to close chromatin conformation, suppressing transcription and silencing tumor suppressor genes. Consequently, HDAC and DNMT inhibitors appeared to reprogram the transcriptional circuit and potentiate anti-tumoral activity. Here, we report that eicosapentaenoic acid (EPA), a fatty acid with anti-cancer properties, inhibited HDAC1 and DNMT expression and activity, thus promoting tumor suppressor gene expression. In hepatocarcinoma cells (HCC) EPA bound and activated PPARγ thus downregulating HDAC1 which sequentially reduced expression of DNMT1, 3A and 3B. At the same time, activated PPARγ physically interacted with DNMT1 and HDAC1 in a CpG island on the Hic-1 gene to assemble PPARγ/DNMT1 and PPARγ/HDAC1 protein complexes, which exited from DNA. When EPA and PPARγ were no longer bound, the protein complexes separated into individual proteins. Consequently, DNMT1 and HDAC1 down-regulation and release from DNA inhibited their activities. Overall, EPA-bound PPARγ induced re-expression of the tumor suppressor gene Hic-1. In the present study PPARγ emerged as a master regulator acting synergistically through diverse targets and ways to reveal the epigenetic action of EPA as an HDAC1 and DNMT1 inhibitor.
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Affiliation(s)
- Veronica Ceccarelli
- Department of Experimental Medicine, P.le L. Severi, 1, University of Perugia, 06132 Perugia, Italy
| | - Simona Ronchetti
- Department of Medicine, P.le L. Severi, 1, University of Perugia, 06132 Perugia, Italy
| | | | - Mario Calvitti
- Department of Experimental Medicine, P.le L. Severi, 1, University of Perugia, 06132 Perugia, Italy
| | - Carlo Riccardi
- Department of Medicine, P.le L. Severi, 1, University of Perugia, 06132 Perugia, Italy
| | - Francesco Grignani
- Department of Medicine, P.le L. Severi, 1, University of Perugia, 06132 Perugia, Italy
| | - Alba Vecchini
- Department of Experimental Medicine, P.le L. Severi, 1, University of Perugia, 06132 Perugia, Italy.
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Dan H, Zhang S, Zhou Y, Guan Q. DNA Methyltransferase Inhibitors: Catalysts For Antitumour Immune Responses. Onco Targets Ther 2019; 12:10903-10916. [PMID: 31849494 PMCID: PMC6913319 DOI: 10.2147/ott.s217767] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 10/02/2019] [Indexed: 12/15/2022] Open
Abstract
Epigenetics is a kind of heritable change that involves the unaltered DNA sequence and can have effects on gene expression. The regulatory mechanism mainly includes DNA methylation, histone modification and non-coding RNA regulation. DNA methylation is currently the most studied aspect of epigenetics. It is widely present in eukaryotic cells and is the most important epigenetic mark in the regulation of gene expression in the cell. DNA methyltransferase inhibitors (DNMTi) have been increasingly recognized in the field of cancer immunotherapy, have been approved for the treatment of acute myeloid leukaemia (AML) and are widely being used in clinical trials of cancer immunotherapies. DNMTi promote the reactivation of tumour suppressor genes, enhance tumour immunogenicity, and stimulate a variety of immune cells to secrete cytokines that exert cytotoxic effects, promote tumour cell death, including macrophages, natural killer (NK) cells and CD8+ T cells, and upregulate major histocompatibility complex (MHC) class I expression levels. Here, we mainly summarize the epigenetics related to DNMTi and their regulation of the antitumour immune response and DNMTi combined with immuno-therapeutics or histone deacetylase inhibitors to demonstrate the great development potential and clinical application value of DNMTi.
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Affiliation(s)
- Huimin Dan
- Gansu Province Key Laboratory of Gastrointestinal Diseases, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu Province, People's Republic of China
| | - Shanshan Zhang
- Gansu Province Key Laboratory of Gastrointestinal Diseases, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu Province, People's Republic of China
| | - Yongning Zhou
- Gansu Province Key Laboratory of Gastrointestinal Diseases, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu Province, People's Republic of China
| | - Quanlin Guan
- Gansu Province Key Laboratory of Gastrointestinal Diseases, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu Province, People's Republic of China
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Michalak EM, Burr ML, Bannister AJ, Dawson MA. The roles of DNA, RNA and histone methylation in ageing and cancer. Nat Rev Mol Cell Biol 2019; 20:573-589. [PMID: 31270442 DOI: 10.1038/s41580-019-0143-1] [Citation(s) in RCA: 360] [Impact Index Per Article: 60.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2019] [Indexed: 12/17/2022]
Abstract
Chromatin is a macromolecular complex predominantly comprising DNA, histone proteins and RNA. The methylation of chromatin components is highly conserved as it helps coordinate the regulation of gene expression, DNA repair and DNA replication. Dynamic changes in chromatin methylation are essential for cell-fate determination and development. Consequently, inherited or acquired mutations in the major factors that regulate the methylation of DNA, RNA and/or histones are commonly observed in developmental disorders, ageing and cancer. This has provided the impetus for the clinical development of epigenetic therapies aimed at resetting the methylation imbalance observed in these disorders. In this Review, we discuss the cellular functions of chromatin methylation and focus on how this fundamental biological process is corrupted in cancer. We discuss methylation-based cancer therapies and provide a perspective on the emerging data from early-phase clinical trial therapies that target regulators of DNA and histone methylation. We also highlight promising therapeutic strategies, including monitoring chromatin methylation for diagnostic purposes and combination epigenetic therapy strategies that may improve immune surveillance in cancer and increase the efficacy of conventional and targeted anticancer drugs.
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Affiliation(s)
- Ewa M Michalak
- Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
| | - Marian L Burr
- Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
| | - Andrew J Bannister
- Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.
| | - Mark A Dawson
- Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia.
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
- Centre for Cancer Research, The University of Melbourne, Melbourne, Australia.
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Di Giacomo AM, Covre A, Finotello F, Rieder D, Danielli R, Sigalotti L, Giannarelli D, Petitprez F, Lacroix L, Valente M, Cutaia O, Fazio C, Amato G, Lazzeri A, Monterisi S, Miracco C, Coral S, Anichini A, Bock C, Nemc A, Oganesian A, Lowder J, Azab M, Fridman WH, Sautès-Fridman C, Trajanoski Z, Maio M. Guadecitabine Plus Ipilimumab in Unresectable Melanoma: The NIBIT-M4 Clinical Trial. Clin Cancer Res 2019; 25:7351-7362. [PMID: 31530631 DOI: 10.1158/1078-0432.ccr-19-1335] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 07/23/2019] [Accepted: 09/13/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE The immunomodulatory activity of DNA hypomethylating agents (DHAs) suggests they may improve the effectiveness of cancer immunotherapies. The phase Ib NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab. PATIENTS AND METHODS Patients with unresectable stage III/IV melanoma received escalating doses of guadecitabine 30, 45, or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on day 1 every 3 weeks, starting 1 week after guadecitabine, for four cycles. Primary endpoints were safety, tolerability, and MTD of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); and exploratory were changes in methylome, transcriptome, and immune contextures in sequential tumor biopsies, and pharmacokinetics. RESULTS Nineteen patients were treated; 84% had grade 3/4 adverse events, and neither dose-limiting toxicities per protocol nor overlapping toxicities were observed. Ir-DCR and ir-ORR were 42% and 26%, respectively. Median CpG site methylation of tumor samples (n = 8) at week 4 (74.5%) and week 12 (75.5%) was significantly (P < 0.05) lower than at baseline (80.3%), with a median of 2,454 (week 4) and 4,131 (week 12) differentially expressed genes. Among the 136 pathways significantly (P < 0.05; Z score >2 or ←2) modulated by treatment, the most frequently activated were immune-related. Tumor immune contexture analysis (n = 11) demonstrated upregulation of HLA class I on melanoma cells, an increase in CD8+, PD-1+ T cells and in CD20+ B cells in posttreatment tumor cores. CONCLUSIONS Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma and has promising immunomodulatory and antitumor activity.
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Affiliation(s)
| | - Alessia Covre
- Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy
| | - Francesca Finotello
- Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Dietmar Rieder
- Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Riccardo Danielli
- Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy
| | - Luca Sigalotti
- Oncogenetics and Functional Oncogenomics Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | | | - Florent Petitprez
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Team Cancer, Immune Control and Escape, Paris, France
- University Paris Descartes Paris 5, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
- Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
- Programme Cartes d'Identitié des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
| | - Laetitia Lacroix
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Team Cancer, Immune Control and Escape, Paris, France
- University Paris Descartes Paris 5, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
- Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
| | - Monica Valente
- Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy
| | - Ornella Cutaia
- Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy
| | - Carolina Fazio
- Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy
| | - Giovanni Amato
- Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy
| | - Andrea Lazzeri
- Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy
| | - Santa Monterisi
- Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy
| | - Clelia Miracco
- Pathology Unit, Department of Medical, Surgical and Neurological Science, University of Siena, S. Maria alle Scotte Hospital, Siena, Italy
| | - Sandra Coral
- Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy
| | - Andrea Anichini
- HumanTumors Immunobiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Christoph Bock
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
- Max Planck Institute for Informatics, Saarbrücken, Germany
| | - Amelie Nemc
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | | | - James Lowder
- Astex Pharmaceuticals Inc., Pleasanton, California
| | | | - Wolf H Fridman
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Team Cancer, Immune Control and Escape, Paris, France
- University Paris Descartes Paris 5, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
- Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
| | - Catherine Sautès-Fridman
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Team Cancer, Immune Control and Escape, Paris, France
- University Paris Descartes Paris 5, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
- Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France
| | - Zlatko Trajanoski
- Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Michele Maio
- Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy.
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Phuengkham H, Ren L, Shin IW, Lim YT. Nanoengineered Immune Niches for Reprogramming the Immunosuppressive Tumor Microenvironment and Enhancing Cancer Immunotherapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1803322. [PMID: 30773696 DOI: 10.1002/adma.201803322] [Citation(s) in RCA: 207] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 01/03/2019] [Indexed: 06/09/2023]
Abstract
Cancer immunotherapies that harness the body's immune system to combat tumors have received extensive attention and become mainstream strategies for treating cancer. Despite promising results, some problems remain, such as the limited patient response rate and the emergence of severe immune-related adverse effects. For most patients, the therapeutic efficacy of cancer immunotherapy is mainly limited by the immunosuppressive tumor microenvironment (TME). To overcome such obstacles in the TME, the immunomodulation of immunosuppressive factors and therapeutic immune cells (e.g., T cells and antigen-presenting cells) should be carefully designed and evaluated. Nanoengineered synthetic immune niches have emerged as highly customizable platforms with a potent capability for reprogramming the immunosuppressive TME. Here, recent developments in nano-biomaterials that are rationally designed to modulate the immunosuppressive TME in a spatiotemporal manner for enhanced cancer immunotherapy which are rationally designed to modulate the immunosuppressive TME in a spatiotemporal manner for enhanced cancer immunotherapy are highlighted.
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Affiliation(s)
- Hathaichanok Phuengkham
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Engineering, and School of Chemical Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
| | - Long Ren
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Engineering, and School of Chemical Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
| | - Il Woo Shin
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Engineering, and School of Chemical Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
| | - Yong Taik Lim
- SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Engineering, and School of Chemical Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
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Pandey MR, Ernstoff MS. Mechanism of resistance to immune checkpoint inhibitors. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:178-188. [PMID: 35582715 PMCID: PMC8992621 DOI: 10.20517/cdr.2018.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 04/16/2019] [Accepted: 05/08/2019] [Indexed: 11/15/2022]
Abstract
Immune checkpoint inhibitors (ICI) have revolutionized the management of cancer over the last decade. Instead of targeting the cancer cell directly these agents work by augmenting the immune response towards tumor. Although they are associated with improved responses compared to traditional treatments in several malignancies, a majority of the patients don't respond to ICIs even when used in the frontline setting. In patients who do respond, a significant number eventually develop resistance. We will review ICI mechanisms of action and resistance. We will also discuss new therapeutic options and combinations with other agents that are currently being evaluated to overcome resistance to ICI.
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Affiliation(s)
- Manu R. Pandey
- Department of Medicine, Roswell Park Comprehensive Cancer Center, NY 14203, USA
| | - Marc S. Ernstoff
- Department of Medicine, Roswell Park Comprehensive Cancer Center, NY 14203, USA
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Schnekenburger M, Dicato M, Diederich MF. Anticancer potential of naturally occurring immunoepigenetic modulators: A promising avenue? Cancer 2019; 125:1612-1628. [PMID: 30840315 DOI: 10.1002/cncr.32041] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 12/29/2018] [Accepted: 01/25/2019] [Indexed: 12/19/2022]
Abstract
The immune system represents the major primary defense line against carcinogenesis and acts by identifying and eradicating nascent transformed cells. A growing body of evidence is indicating that aberrant epigenetic reprogramming plays a key role in tumor immune escape through: 1) impaired efficient recognition of neoplastic cells by the immune system, resulting from a downregulation or loss of the expression of tumor-associated antigens, human leukocyte antigens, antigen processing and presenting machinery, and costimulatory molecule genes; 2) aberrant expression of immune checkpoint proteins and their ligands; and 3) modification of cytokine profiles and tumor-associated immune cell populations toward an immunosuppressive state in the tumor microenvironment. Consistent with the inherent reversibility of epigenetic alterations, epigenetic drugs, including DNA methyltransferase and histone deacetylase inhibitors, have the unique potential to favorably modify the tumor microenvironment, restore tumor recognition and stimulate an antitumor immune response. The objective of this review is to highlight selected, naturally occurring epigenetic modulators, namely, butyrate, curcumin, (-)-epigallocatechin-3-gallate, resveratrol, romidepsin, and trichostatin A, with a special focus on their antitumor immune properties.
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Affiliation(s)
- Michael Schnekenburger
- Laboratory of Molecular and Cellular Biology of Cancer, Kirchberg Hospital, Luxembourg, Luxembourg
| | - Mario Dicato
- Laboratory of Molecular and Cellular Biology of Cancer, Kirchberg Hospital, Luxembourg, Luxembourg
| | - Marc F Diederich
- Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
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Criscuolo D, Morra F, Giannella R, Visconti R, Cerrato A, Celetti A. New combinatorial strategies to improve the PARP inhibitors efficacy in the urothelial bladder Cancer treatment. J Exp Clin Cancer Res 2019; 38:91. [PMID: 30791940 PMCID: PMC6385418 DOI: 10.1186/s13046-019-1089-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 02/06/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Novel therapeutic strategies are urgently needed for the treatment of metastatic Urothelial Bladder Cancer. DNA damaging repair (DDR) targeting has been introduced in cinical trials for bladder cancer patients that carry alterations in homologous DNA repair genes, letting to envisage susceptibility to the Poly (adenosine diphosphate [ADP]) ribose polymerase (PARP) inhibitors. MAIN BODY PARP inhibition, by amplifying the DNA damage, augments the mutational burden and promotes the immune priming of the tumor by increasing the neoantigen exposure and determining upregulation of programmed death ligand 1 (PD-L1) expression. Thus, the combination of PARP-inhibition and the PD/PD-L1 targeting may represent a compelling strategy to treat bladder cancer and has been introduced in recent clinical trials. The targeting of DDR has been also used in combination with epigenetic drugs able to modulate the expression of genes involved in DDR, and also able to act as immunomodulator agents suggesting their use in combination with immune-checkpoint inhibitors. CONCLUSION In conclusion, it may be envisaged the combination of three classes of drugs to treat bladder cancer, by targeting the DDR process in a tumor context of DDR defect, together with epigenetic agents and immune-checkpoint inhibitors, whose association may amplify the effects and reduce the doses and the toxicity of each single drug.
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Affiliation(s)
- Daniela Criscuolo
- Institute for the Experimental Endocrinology and Oncology, Research National Council, CNR, Naples, Italy
| | - Francesco Morra
- 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
| | - Aniello Cerrato
- Institute for the Experimental Endocrinology and Oncology, Research National Council, CNR, Naples, Italy
| | - Angela Celetti
- Institute for the Experimental Endocrinology and Oncology, Research National Council, CNR, Naples, Italy
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Di Giacomo AM, Covre A, Giacobini G, Ibrahim R, Lyman J, Natali PG, Maio M. The Italian Network for Tumor Bio-Immunotherapy (NIBIT) Foundation: ongoing and prospective activities in immuno-oncology. Cancer Immunol Immunother 2019; 68:143-150. [PMID: 30564888 PMCID: PMC11028314 DOI: 10.1007/s00262-018-2286-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 12/11/2018] [Indexed: 01/10/2023]
Abstract
The ongoing revolution in cancer immunotherapy stems from the knowledge that distinct immune-checkpoints regulate the physiological crosstalk between and among immune cells by delivering inhibitory or activating signals. These notions, and the availability of mAb directed to diverse immune-checkpoint molecules, have led to a significant clinical improvement in cancer treatment. In this scenario, further achievements are undoubtedly to be expected from the contribution of novel, proof-of-principle clinical trials designed to explore the therapeutic efficacy of new immunotherapy-based combinations and treatment sequences. Along these lines, the clinical translation of pre-clinical evidence generated by non-profit research entities is likely to provide a significant contribution to gaining new insights that will further boost the field of cancer immunotherapy. To pursue this goal, and to provide comprehensive educational programs in immune-oncology (I-O), several national and global networks have been revitalized or newly established in recent years. This rapidly evolving scenario led the Board of Directors of the Italian Network of Tumor Bio-Immunotherapy (NIBIT) to establish the NIBIT Foundation. This Focused Research Review summarizes the main ongoing and prospective I-O activities of the NIBIT Foundation.
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Affiliation(s)
- Anna Maria Di Giacomo
- Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Viale Mario Bracci, 16, 53100, Siena, Italy.
| | - Alessia Covre
- Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Viale Mario Bracci, 16, 53100, Siena, Italy
| | - Gianluca Giacobini
- Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Viale Mario Bracci, 16, 53100, Siena, Italy
| | - Ramy Ibrahim
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
| | - Jaclyn Lyman
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
| | - Pier Giorgio Natali
- Center on Aging Sciences and Translational Medicine (CeSI-MeT), Gabriele d' Annunzio University, Chieti, Italy
| | - Michele Maio
- Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Viale Mario Bracci, 16, 53100, Siena, Italy
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Fazio C, Covre A, Cutaia O, Lofiego MF, Tunici P, Chiarucci C, Cannito S, Giacobini G, Lowder JN, Ferraldeschi R, Taverna P, Di Giacomo AM, Coral S, Maio M. Immunomodulatory Properties of DNA Hypomethylating Agents: Selecting the Optimal Epigenetic Partner for Cancer Immunotherapy. Front Pharmacol 2018; 9:1443. [PMID: 30581389 PMCID: PMC6293200 DOI: 10.3389/fphar.2018.01443] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 11/22/2018] [Indexed: 11/14/2022] Open
Abstract
DNA hypomethylating agents (DHAs) play a well-acknowledged role in potentiating the immunogenicity and the immune recognition of neoplastic cells. This immunomodulatory activity of DHAs is linked to their ability to induce or to up-regulate on neoplastic cells the expression of a variety of immune molecules that play a crucial role in host-tumor immune interactions. To further investigate the clinical potential of diverse epigenetic compounds when combined with immunotherapeutic strategies, we have now compared the tumor immunomodulatory properties of the first generation DHAs, azacytidine (AZA) and decitabine (DAC) and of the next generation DHA, guadecitabine. To this end, human melanoma and hematological cancer cells were treated in vitro with 1 μM guadecitabine, DAC or AZA and then studied by molecular and flow cytometry analyses for changes in their baseline expression of selected immune molecules involved in different mechanism(s) of immune recognition. Results demonstrated a stronger DNA hypomethylating activity of guadecitabine and DAC, compared to AZA that associated with stronger immunomodulatory activities. Indeed, the mRNA expression of cancer testis antigens, immune-checkpoint blocking molecules, immunostimulatory cytokines, involved in NK and T cell signaling and recruiting, and of genes involved in interferon pathway was higher after guadecitabine and DAC compared to AZA treatment. Moreover, a stronger up-regulation of the constitutive expression of HLA class I antigens and of Intercellular Adhesion Molecule-1 was observed with guadecitabine and DAC compared to AZA. Guadecitabine and DAC seem to represent the optimal combination partners to improve the therapeutic efficacy of immunotherapeutic agents in combination/sequencing clinical studies.
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Affiliation(s)
- Carolina Fazio
- Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
| | - Alessia Covre
- Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
| | - Ornella Cutaia
- Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
| | - Maria Fortunata Lofiego
- Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
| | - Patrizia Tunici
- Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
| | - Carla Chiarucci
- Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
| | - Sara Cannito
- Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
| | - Gianluca Giacobini
- Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
| | - James N Lowder
- Astex Pharmaceuticals, Inc., Pleasanton, CA, United States
| | | | - Pietro Taverna
- Astex Pharmaceuticals, Inc., Pleasanton, CA, United States
| | - Anna Maria Di Giacomo
- Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
| | - Sandra Coral
- Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
| | - Michele Maio
- Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
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41
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Liu Z, Gao Y, Li X. Cancer epigenetics and the potential of epigenetic drugs for treating solid tumors. Expert Rev Anticancer Ther 2018; 19:139-149. [PMID: 30470148 DOI: 10.1080/14737140.2019.1552139] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: Epigenetic modification without DNA sequence mutation plays an important role in cancer development. Some small molecular inhibitors targeting key epigenetic molecules have been approved by the Food and Drug Administration to treat hematological malignancies. However, the anticancer effects of these drugs on solid tumors are not satisfactory, and the mechanisms of action remain largely unknown. Areas covered: The review summarizes the latest research on cancer epigenetics and discusses the potentials and limitations of using epigenetic drugs to treat solid tumors. An analysis of possible reasons for epigenetic drug treatment failure in solid tumors in some clinical trials is discussed along with prospects for future development. Expert commentary: Next-generation small molecule inhibitors will target novel epigenetic regulators with high cancer specificity. Combined modalities exploiting epigenetic drugs with chemo-/radiotherapy, molecular-targeting drugs, and immunotherapy will be able to effectively treat solid tumors in the near future.
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Affiliation(s)
- Zhenghui Liu
- a Xiangya Hospital, Central South University , Changsha , Hunan , China
| | - Yingxue Gao
- a Xiangya Hospital, Central South University , Changsha , Hunan , China
| | - Xiong Li
- a Xiangya Hospital, Central South University , Changsha , Hunan , China
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42
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Herrera AF. Where does PD-1 blockade fit in HL therapy? HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2018; 2018:213-220. [PMID: 30504313 PMCID: PMC6246012 DOI: 10.1182/asheducation-2018.1.213] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Genetic alterations of the PD-L1/PD-L2 locus on chromosome 9p24.1 are a defining biological feature of classical Hodgkin lymphoma (HL). The resulting programmed death-ligand 1 (PD-L1) expression on Hodgkin Reed-Sternberg cells as well as the PD-L1 expressed in the HL microenvironment result in an ineffective host antitumor immune response and make HL a ripe target for programmed cell death-1 (PD-1) blockade. Anti-PD-1 antibody monotherapy has been effective and well tolerated in patients with relapsed or refractory (rel/ref) HL, with the majority of patients experiencing an objective response (approximately two-thirds of patients) and a median duration of response of 16.6 months in the study with the longest follow-up. Based on these data, nivolumab and pembrolizumab were approved by the US Food and Drug Administration (FDA) for the treatment of advanced rel/ref HL. Evidence has emerged that patients with HL benefit from continued PD-1 blockade beyond disease progression according to traditionally defined response criteria, and that the addition of, or switch to, chemotherapy after anti-PD-1 antibody failure can potentially re-induce clinical response. Subsequent studies have evaluated novel anti-PD-1-based combination regimens as well as the use of anti-PD-1 antibody therapy earlier in the course of a HL patient's therapy, including first salvage therapy for rel/ref disease (eg, nivolumab plus brentuximab vedotin) and even first-line treatment (eg, nivolumab added to doxorubicin, vinblastine, dacarbazine chemotherapy). The current role of PD-1 blockade in HL is as monotherapy in patients with advanced rel/ref disease, but the results of ongoing studies and the evolving treatment landscape in HL will determine the role of PD-1 blockade in the future.
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Affiliation(s)
- Alex F Herrera
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
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43
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Sasidharan Nair V, El Salhat H, Taha RZ, John A, Ali BR, Elkord E. DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer. Clin Epigenetics 2018; 10:78. [PMID: 29983831 PMCID: PMC6003083 DOI: 10.1186/s13148-018-0512-1] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 06/04/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND High expression of immune checkpoints in tumor microenvironment plays significant roles in inhibiting anti-tumor immunity, which is associated with poor prognosis and cancer progression. Major epigenetic modifications in both DNA and histone could be involved in upregulation of immune checkpoints in cancer. METHODS Expressions of different immune checkpoint genes and PD-L1 were assessed using qRT-PCR, and the underlying epigenetic modifications including CpG methylation and repressive histone abundance were determined using bisulfite sequencing, and histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) chromatin immunoprecipitation assays (ChIP), respectively. RESULTS We first assessed the expression level of six immune checkpoints/ligands and found that PD-1, CTLA-4, TIM-3, and LAG-3 were significantly upregulated in breast tumor tissues (TT), compared with breast normal tissues (NT). We investigated the epigenetic modifications beyond this upregulation in immune checkpoint genes. Interestingly, we found that CpG islands in the promoter regions of PD-1, CTLA-4, and TIM-3 were significantly hypomethylated in tumor compared with normal tissues. Additionally, CpG islands of PD-L1 promoter were completely demethylated (100%), LAG-3 were highly hypomethylated (80-90%), and TIGIT were poorly hypomethylated (20-30%), in both NT and TT. These demethylation findings are in accordance with the relative expression data that, out of all these genes, PD-L1 was highly expressed and completely demethylated and TIGIT was poorly expressed and hypermethylated in both NT and TT. Moreover, bindings of H3K9me3 and H3K27me3 were found to be reduced in the promoter loci of PD-1, CTLA-4, TIM-3, and LAG-3 in tumor tissues. CONCLUSION Our data demonstrate that both DNA and histone modifications are involved in upregulation of PD-1, CTLA-4, TIM-3, and LAG-3 in breast tumor tissue and these epigenetic modifications could be useful as diagnostic/prognostic biomarkers and/or therapeutic targets in breast cancer.
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Affiliation(s)
- Varun Sasidharan Nair
- Cancer Research Center, Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Haytham El Salhat
- Oncology Department, Al Noor Hospital, Abu Dhabi, United Arab Emirates
- Oncology Department, Tawam Hospital, Al Ain, United Arab Emirates
| | - Rowaida Z. Taha
- Cancer Research Center, Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Anne John
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Bassam R. Ali
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Eyad Elkord
- Cancer Research Center, Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
- Institute of Cancer Sciences, University of Manchester, Manchester, UK
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44
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Xu F, Jin T, Zhu Y, Dai C. Immune checkpoint therapy in liver cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:110. [PMID: 29843754 PMCID: PMC5975687 DOI: 10.1186/s13046-018-0777-4] [Citation(s) in RCA: 279] [Impact Index Per Article: 39.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 04/28/2018] [Indexed: 02/06/2023]
Abstract
Immune checkpoints include stimulatory and inhibitory checkpoint molecules. In recent years, inhibitory checkpoints, including cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand 1 (PD-L1), have been identified to suppress anti-tumor immune responses in solid tumors. Novel drugs targeting immune checkpoints have succeeded in cancer treatment. Specific PD-1 blockades were approved for treatment of melanoma in 2014 and for treatment of non-small-cell lung cancer in 2015 in the United States, European Union, and Japan. Preclinical and clinical studies show immune checkpoint therapy provides survival benefit for greater numbers of patients with liver cancer, including hepatocellular carcinoma and cholangiocarcinoma, two main primary liver cancers. The combination of anti-PD-1/PD-L1 with anti-CTLA-4 antibodies is being evaluated in phase 1, 2 or 3 trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. In addition, studies on activating co-stimulatory receptors to enhance anti-tumor immune responses have increased our understanding regarding this immunotherapy in liver cancer. Epigenetic modulations of checkpoints for improving the tumor microenvironment also expand our knowledge of potential therapeutic targets in improving the tumor microenvironment and restoring immune recognition and immunogenicity. In this review, we summarize current knowledge and recent developments in immune checkpoint-based therapies for the treatment of hepatocellular carcinoma and cholangiocarcinoma and attempt to clarify the mechanisms underlying its effects.
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Affiliation(s)
- Feng Xu
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital affiliated to China Medical University, Shenyang, 110004, Liaoning, China.,Department of Surgery, University of Colorado Anschutz Medical Campus, RC1-North Building, P18-8116, Aurora, CO, 80045, USA
| | - Tianqiang Jin
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital affiliated to China Medical University, Shenyang, 110004, Liaoning, China
| | - Yuwen Zhu
- Department of Surgery, University of Colorado Anschutz Medical Campus, RC1-North Building, P18-8116, Aurora, CO, 80045, USA.
| | - Chaoliu Dai
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital affiliated to China Medical University, Shenyang, 110004, Liaoning, China.
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45
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Abstract
Targeting DNA hypermethylation, using nucleoside analogs, is an efficient approach to reprogram cancer cell epigenome leading to reduced proliferation, increased differentiation, recognition by the immune system, and ultimately cancer cell death. DNA methyltransferase inhibitors have been approved for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myelogenous leukemia. To improve clinical efficacy and overcome mechanisms of drug resistance, a second generation of DNA methyltransferase inhibitors has been designed and is currently in clinical trials. Although efficient in monotherapy against hematologic malignancies, the potential of DNA methyltransferase inhibitors to synergize with small molecules targeting chromatin or immunotherapy will provide additional opportunities for their future clinical application against leukemia and solid tumors.
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46
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Daifuku R, Grimes S, Stackhouse M. NUC041, a Prodrug of the DNA Methytransferase Inhibitor 5-aza-2',2'-Difluorodeoxycytidine (NUC013), Leads to Tumor Regression in a Model of Non-Small Cell Lung Cancer. Pharmaceuticals (Basel) 2018; 11:ph11020036. [PMID: 29690576 PMCID: PMC6027359 DOI: 10.3390/ph11020036] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 04/17/2018] [Accepted: 04/18/2018] [Indexed: 01/10/2023] Open
Abstract
5-aza-2′,2′-difluorodeoxycytidine (NUC013) has been shown to be significantly safer and more effective than decitabine in xenograft models of human leukemia and colon cancer. However, it suffers from a similar short half-life as other DNA methyltransferase inhibitors with a 5-azacytosine base, which is problematic for nucleosides that primarily target tumor cells in S phase. Because of the relative instability of 5-azanucleosides, a prodrug approach was developed to improve the pharmacology of NUC013. NUC013 was conjugated with trimethylsilanol (TMS) at the 3′ and 5′ position of the sugar, rendering the molecule hydrophobic and producing 3′,5′-di-trimethylsilyl-2′,2′-difluoro-5-azadeoxycytidine (NUC041). NUC041 was designed to be formulated in a hydrophobic vehicle, protecting it from deamination and hydrolysis. In contact with blood, the TMS moieties are readily hydrolyzed to release NUC013. The half-life of NUC013 administered intravenously in mice is 20.1 min, while that of NUC013 derived from intramuscular NUC041 formulated in a pegylated-phospholipid depot is 3.4 h. In a NCI-H460 xenograft of non-small cell lung cancer, NUC013 was shown to significantly inhibit tumor growth and improve survival. Treatment with NUC041 also led to significant tumor growth inhibition. However, NUC041-treated mice had significantly more tumors ulcerate than either NUC013 treated mice or saline control mice, and such ulceration occurred at significantly lower tumor volumes. In these nude mice, tumor regression was likely mediated by the derepression of the tumor suppressor gene p53 and resultant activation of natural killer (NK) cells.
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Affiliation(s)
- Richard Daifuku
- Epigenetics Pharma, 9270 SE 36th Pl, Mercer Island, WA 98040, USA.
| | - Sheila Grimes
- Southern Research, 2000 9th Avenue South, Birmingham, AL 35205, USA.
| | - Murray Stackhouse
- Southern Research, 2000 9th Avenue South, Birmingham, AL 35205, USA.
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47
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Conte M, De Palma R, Altucci L. HDAC inhibitors as epigenetic regulators for cancer immunotherapy. Int J Biochem Cell Biol 2018. [PMID: 29535070 DOI: 10.1016/j.biocel.2018.03.004] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In recent years, anti-tumor immunotherapy has shown promising results, and immune-oncology is now emerging as the fourth major wave in the treatment of tumors after radiotherapy, chemotherapy and molecular targeted therapy. Understanding the impact of the immune system on neoplastic cells is crucial to improve its effectiveness against cancer. The stratification of patients who might benefit from immunotherapy as well as the personalization of medicine have contributed to the discovery of new immunotherapeutic targets and molecules. In the present review, we discuss the mechanistic role of histone deacetylase inhibitors (HDACi) as potential immunomodulating agents to treat cancer. Our current understanding of the use of HDACi in combination with various immunotherapeutic approaches, such as immunomodulating agents and cancer vaccines, is also addressed. The potential clinical applications of the growing number of novel epigenetic drugs for cancer immunotherapy are widening, and some of these therapies are already in clinical trials.
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Affiliation(s)
| | - Raffaele De Palma
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Vico L. De Crecchio 7, 80138, Naples, Italy
| | - Lucia Altucci
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Vico L. De Crecchio 7, 80138, Naples, Italy.
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48
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Dockry É, O'Leary S, Gleeson LE, Lyons J, Keane J, Gray SG, Doherty DG. Epigenetic induction of CD1d expression primes lung cancer cells for killing by invariant natural killer T cells. Oncoimmunology 2018; 7:e1428156. [PMID: 29872551 DOI: 10.1080/2162402x.2018.1428156] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 01/08/2018] [Accepted: 01/09/2018] [Indexed: 01/22/2023] Open
Abstract
Immunotherapies that target CD1d-restricted invariant NKT (iNKT) cells can prevent tumor growth in murine models but trials in humans have shown limited clinical efficacy. Here, we show that iNKT cells are depleted from blood and bronchial lavage samples from patients with non-small cell lung cancer (NSCLC) suggesting a role for these cells in immunity against NSCLC. We interrogated the Lung Cancer Explorer and Kaplan-Meier Plotter databases of NSCLC patients and found that pulmonary CD1d expression is reduced in patients with NSCLC and that low expression of CD1d mRNA is significantly associated with poor patient survival. We hypothesized that CD1d expression in NSCLC is epigenetically regulated and can be modulated using epigenetic targeting therapies. Treatment of the CD1d-negative NSCLC cell lines, A549 and SK-MES-1, with DNA methyltransferase inhibitors and histone deacetylase inhibitors resulted in a dose-dependent induction of CD1d mRNA and protein expression. Chromatin immunoprecipitation analysis indicated that this induction of CD1d expression directly involved chromatin remodelling. Induction of CD1d expression by A549 and SK-MES-1 cells using therapeutic low doses of DNA methyltransferase inhibitors and histone deacetylase inhibitors made them targets for iNKT cell-mediated cytolytic degranulation. Thus, epigenetic manipulation of CD1d expression may augment the efficacy of iNKT cell-based immunotherapies for NSCLC.
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Affiliation(s)
- Éilis Dockry
- Department of Immunology, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.,Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Seónadh O'Leary
- Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Laura E Gleeson
- Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.,Department of Respiratory Medicine, St. James' Hospital, Dublin, Ireland
| | - Judith Lyons
- Department of Respiratory Medicine, St. James' Hospital, Dublin, Ireland
| | - Joseph Keane
- Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.,Department of Respiratory Medicine, St. James' Hospital, Dublin, Ireland
| | - Steven G Gray
- Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Derek G Doherty
- Department of Immunology, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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49
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DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer. Nat Commun 2018; 9:248. [PMID: 29339738 PMCID: PMC5770411 DOI: 10.1038/s41467-017-02630-w] [Citation(s) in RCA: 184] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 12/15/2017] [Indexed: 12/15/2022] Open
Abstract
Potentiating anti-tumor immunity by inducing tumor inflammation and T cell-mediated responses are a promising area of cancer therapy. Immunomodulatory agents that promote these effects function via a wide variety of mechanisms, including upregulation of antigen presentation pathways. Here, we show that major histocompatibility class-I (MHC-I) genes are methylated in human breast cancers, suppressing their expression. Treatment of breast cancer cell lines with a next-generation hypomethylating agent, guadecitabine, upregulates MHC-I expression in response to interferon-γ. In murine tumor models of breast cancer, guadecitabine upregulates MHC-I in tumor cells promoting recruitment of CD8+ T cells to the microenvironment. Finally, we show that MHC-I genes are upregulated in breast cancer patients treated with hypomethylating agents. Thus, the immunomodulatory effects of hypomethylating agents likely involve upregulation of class-I antigen presentation to potentiate CD8+ T cell responses. These strategies may be useful to potentiate anti-tumor immunity and responses to checkpoint inhibition in immune-refractory breast cancers. Immunotherapy often fails as a single option treatment in cancer. Here, the authors show that targeting of DNA methyltransferases, such as DNMT1, can potentiate anti-tumor immunity and response to checkpoint inhibition by increasing MHC gene expression and the recruitment of CD8+ T cells.
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50
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Buoncervello M, Romagnoli G, Buccarelli M, Fragale A, Toschi E, Parlato S, Lucchetti D, Macchia D, Spada M, Canini I, Sanchez M, Falchi M, Musella M, Biffoni M, Belardelli F, Capone I, Sgambato A, Vitiani LR, Gabriele L. IFN-α potentiates the direct and immune-mediated antitumor effects of epigenetic drugs on both metastatic and stem cells of colorectal cancer. Oncotarget 2018; 7:26361-73. [PMID: 27028869 PMCID: PMC5041985 DOI: 10.18632/oncotarget.8379] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 03/02/2016] [Indexed: 01/29/2023] Open
Abstract
Epigenetic alterations, including dysregulated DNA methylation and histone modifications, govern the progression of colorectal cancer (CRC). Cancer cells exploit epigenetic regulation to control cellular pathways, including apoptotic and metastatic signals. Since aberrations in epigenome can be pharmacologically reversed by DNA methyltransferase and histone deacetylase inhibitors, epigenetics in combination with standard agents are currently envisaged as a new therapeutic frontier in cancer, expected to overcome drug resistance associated with current treatments. In this study, we challenged this idea and demonstrated that the combination of azacitidine and romidepsin with IFN-α owns a high therapeutic potential, targeting the most aggressive cellular components of CRC, such as metastatic cells and cancer stem cells (CSCs), via tight control of key survival and death pathways. Moreover, the antitumor efficacy of this novel pharmacological approach is associated with induction of signals of immunogenic cell death. Of note, a previously undisclosed key role of IFN-α in inducing both antiproliferative and pro-apoptotic effects on CSCs of CRC was also found. Overall, these findings open a new frontier on the suitability of IFN-α in association with epigenetics as a novel and promising therapeutic approach for CRC management.
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Affiliation(s)
- Maria Buoncervello
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Giulia Romagnoli
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Mariachiara Buccarelli
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Alessandra Fragale
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Elena Toschi
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Stefania Parlato
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Donatella Lucchetti
- Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, 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
| | - Irene Canini
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Massimo Sanchez
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Mario Falchi
- National AIDS Center, Istituto Superiore di Sanità, Rome, Italy
| | - Martina Musella
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Mauro Biffoni
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Filippo Belardelli
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Imerio Capone
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Alessandro Sgambato
- Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Lucia Ricci Vitiani
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Lucia Gabriele
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
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