Enhanced Anticancer Effect of a Combination of S-adenosylmethionine (SAM) and Immune Checkpoint Inhibitor (ICPi) in a Syngeneic Mouse Model of Advanced Melanoma
Immune checkpoint inhibitors (ICPi) targeting the PD-1/PD-L1 pathway have shown marked success in patients with advanced melanoma. However, 60–70% of patients fail to respond, warranting a therapeutic intervention that could increase response rates. We and others have shown that S-adenosylmethionine...
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Frontiers Media S.A.
2020-09-01
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Series: | Frontiers in Oncology |
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Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.01361/full |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ali Mehdi Ali Mehdi Ali Mehdi Mikhael Attias Mikhael Attias Niaz Mahmood Niaz Mahmood Niaz Mahmood Ani Arakelian Ani Arakelian Catalin Mihalcioiu Ciriaco A. Piccirillo Ciriaco A. Piccirillo Ciriaco A. Piccirillo Ciriaco A. Piccirillo Ciriaco A. Piccirillo Moshe Szyf Shafaat Ahmed Rabbani Shafaat Ahmed Rabbani Shafaat Ahmed Rabbani Shafaat Ahmed Rabbani Shafaat Ahmed Rabbani |
spellingShingle |
Ali Mehdi Ali Mehdi Ali Mehdi Mikhael Attias Mikhael Attias Niaz Mahmood Niaz Mahmood Niaz Mahmood Ani Arakelian Ani Arakelian Catalin Mihalcioiu Ciriaco A. Piccirillo Ciriaco A. Piccirillo Ciriaco A. Piccirillo Ciriaco A. Piccirillo Ciriaco A. Piccirillo Moshe Szyf Shafaat Ahmed Rabbani Shafaat Ahmed Rabbani Shafaat Ahmed Rabbani Shafaat Ahmed Rabbani Shafaat Ahmed Rabbani Enhanced Anticancer Effect of a Combination of S-adenosylmethionine (SAM) and Immune Checkpoint Inhibitor (ICPi) in a Syngeneic Mouse Model of Advanced Melanoma Frontiers in Oncology DNA methylation melanoma S-adenosylmethionine anti-PD-1 immunity immune checkpoint inhibitors |
author_facet |
Ali Mehdi Ali Mehdi Ali Mehdi Mikhael Attias Mikhael Attias Niaz Mahmood Niaz Mahmood Niaz Mahmood Ani Arakelian Ani Arakelian Catalin Mihalcioiu Ciriaco A. Piccirillo Ciriaco A. Piccirillo Ciriaco A. Piccirillo Ciriaco A. Piccirillo Ciriaco A. Piccirillo Moshe Szyf Shafaat Ahmed Rabbani Shafaat Ahmed Rabbani Shafaat Ahmed Rabbani Shafaat Ahmed Rabbani Shafaat Ahmed Rabbani |
author_sort |
Ali Mehdi |
title |
Enhanced Anticancer Effect of a Combination of S-adenosylmethionine (SAM) and Immune Checkpoint Inhibitor (ICPi) in a Syngeneic Mouse Model of Advanced Melanoma |
title_short |
Enhanced Anticancer Effect of a Combination of S-adenosylmethionine (SAM) and Immune Checkpoint Inhibitor (ICPi) in a Syngeneic Mouse Model of Advanced Melanoma |
title_full |
Enhanced Anticancer Effect of a Combination of S-adenosylmethionine (SAM) and Immune Checkpoint Inhibitor (ICPi) in a Syngeneic Mouse Model of Advanced Melanoma |
title_fullStr |
Enhanced Anticancer Effect of a Combination of S-adenosylmethionine (SAM) and Immune Checkpoint Inhibitor (ICPi) in a Syngeneic Mouse Model of Advanced Melanoma |
title_full_unstemmed |
Enhanced Anticancer Effect of a Combination of S-adenosylmethionine (SAM) and Immune Checkpoint Inhibitor (ICPi) in a Syngeneic Mouse Model of Advanced Melanoma |
title_sort |
enhanced anticancer effect of a combination of s-adenosylmethionine (sam) and immune checkpoint inhibitor (icpi) in a syngeneic mouse model of advanced melanoma |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2020-09-01 |
description |
Immune checkpoint inhibitors (ICPi) targeting the PD-1/PD-L1 pathway have shown marked success in patients with advanced melanoma. However, 60–70% of patients fail to respond, warranting a therapeutic intervention that could increase response rates. We and others have shown that S-adenosylmethionine (SAM), a universal methyl donor, has significant anticancer effects in numerous cancers previously; however, its effect on melanoma progression has not been evaluated. Interestingly, SAM was reported to be essential for T cell activation and proliferation and, thus, could potentially cooperate with ICPi and block melanoma progression. In this study, we examined the antitumor effects of SAM and ICPi alone and in combination in a well-established melanoma mouse model wherein syngeneic C57BL/6 mouse were subcutaneously (orthotopic) injected with B16-F1 cells. Treatment of mice with either SAM or anti-PD-1 antibody alone resulted in significant reduction in tumor volumes and weights; effects that were highest in mice treated with a combination of SAM+anti-PD-1. RNA-sequencing analysis of the primary tumors showed numerous differentially expressed genes (DEGs) following treatment with SAM+anti-PD-1, which was shown to downregulate cancer, MAPK, and tyrosine kinase pathways. Indeed, SAM+anti-PD-1 reversed the aberrant expression of some known melanoma genes. Tumor immunophenotyping revealed the SAM+anti-PD-1 combination was significantly more effective than either SAM or anti-PD-1 as the CD8+ T cells had higher activation, proliferation, and cytokine production compared to all other groups. This study shows that the combination of currently approved agents SAM and ICPi can effectively block melanoma via alteration of key genes/pathways implicated in cancer and immune response pathways, providing the rationale for the initiation of clinical trials with SAM and ICPi. |
topic |
DNA methylation melanoma S-adenosylmethionine anti-PD-1 immunity immune checkpoint inhibitors |
url |
https://www.frontiersin.org/article/10.3389/fonc.2020.01361/full |
work_keys_str_mv |
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doaj-486e47e75404430eac9ff29cf14a5c3d2020-11-25T03:41:08ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-09-011010.3389/fonc.2020.01361544850Enhanced Anticancer Effect of a Combination of S-adenosylmethionine (SAM) and Immune Checkpoint Inhibitor (ICPi) in a Syngeneic Mouse Model of Advanced MelanomaAli Mehdi0Ali Mehdi1Ali Mehdi2Mikhael Attias3Mikhael Attias4Niaz Mahmood5Niaz Mahmood6Niaz Mahmood7Ani Arakelian8Ani Arakelian9Catalin Mihalcioiu10Ciriaco A. Piccirillo11Ciriaco A. Piccirillo12Ciriaco A. Piccirillo13Ciriaco A. Piccirillo14Ciriaco A. Piccirillo15Moshe Szyf16Shafaat Ahmed Rabbani17Shafaat Ahmed Rabbani18Shafaat Ahmed Rabbani19Shafaat Ahmed Rabbani20Shafaat Ahmed Rabbani21Department of Medicine, McGill University, Montreal, QC, CanadaHuman Genetics, McGill University, Montreal, QC, CanadaProgram in Metabolic Disorders and Complications (MeDiC), Research Institute of the McGill University Health Centre, Montreal, QC, CanadaDepartment of Medicine, McGill University, Montreal, QC, CanadaMicrobiology & Immunology, McGill University, Montreal, QC, CanadaDepartment of Medicine, McGill University, Montreal, QC, CanadaProgram in Metabolic Disorders and Complications (MeDiC), Research Institute of the McGill University Health Centre, Montreal, QC, CanadaExperimental Medicine, McGill University, Montreal, QC, CanadaDepartment of Medicine, McGill University, Montreal, QC, CanadaProgram in Metabolic Disorders and Complications (MeDiC), Research Institute of the McGill University Health Centre, Montreal, QC, CanadaDepartment of Oncology, McGill University, Montreal, QC, CanadaDepartment of Medicine, McGill University, Montreal, QC, CanadaMicrobiology & Immunology, McGill University, Montreal, QC, CanadaExperimental Medicine, McGill University, Montreal, QC, CanadaProgram in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montreal, QC, CanadaCentre of Excellence in Translational Immunology (CETI), Montreal, QC, CanadaDepartment of Pharmacology, McGill University, Montreal, QC, CanadaDepartment of Medicine, McGill University, Montreal, QC, CanadaHuman Genetics, McGill University, Montreal, QC, CanadaProgram in Metabolic Disorders and Complications (MeDiC), Research Institute of the McGill University Health Centre, Montreal, QC, CanadaExperimental Medicine, McGill University, Montreal, QC, CanadaDepartment of Oncology, McGill University, Montreal, QC, CanadaImmune checkpoint inhibitors (ICPi) targeting the PD-1/PD-L1 pathway have shown marked success in patients with advanced melanoma. However, 60–70% of patients fail to respond, warranting a therapeutic intervention that could increase response rates. We and others have shown that S-adenosylmethionine (SAM), a universal methyl donor, has significant anticancer effects in numerous cancers previously; however, its effect on melanoma progression has not been evaluated. Interestingly, SAM was reported to be essential for T cell activation and proliferation and, thus, could potentially cooperate with ICPi and block melanoma progression. In this study, we examined the antitumor effects of SAM and ICPi alone and in combination in a well-established melanoma mouse model wherein syngeneic C57BL/6 mouse were subcutaneously (orthotopic) injected with B16-F1 cells. Treatment of mice with either SAM or anti-PD-1 antibody alone resulted in significant reduction in tumor volumes and weights; effects that were highest in mice treated with a combination of SAM+anti-PD-1. RNA-sequencing analysis of the primary tumors showed numerous differentially expressed genes (DEGs) following treatment with SAM+anti-PD-1, which was shown to downregulate cancer, MAPK, and tyrosine kinase pathways. Indeed, SAM+anti-PD-1 reversed the aberrant expression of some known melanoma genes. Tumor immunophenotyping revealed the SAM+anti-PD-1 combination was significantly more effective than either SAM or anti-PD-1 as the CD8+ T cells had higher activation, proliferation, and cytokine production compared to all other groups. This study shows that the combination of currently approved agents SAM and ICPi can effectively block melanoma via alteration of key genes/pathways implicated in cancer and immune response pathways, providing the rationale for the initiation of clinical trials with SAM and ICPi.https://www.frontiersin.org/article/10.3389/fonc.2020.01361/fullDNA methylationmelanomaS-adenosylmethionineanti-PD-1immunityimmune checkpoint inhibitors |