Enhanced Anticancer Effect of a Combination of S-adenosylmethionine (SAM) and Immune Checkpoint Inhibitor (ICPi) in a Syngeneic Mouse Model of Advanced Melanoma.

Ali Mehdi,Catalin Mihalcioiu,Mikhael Attias,Ciriaco A Piccirillo,Shafaat Ahmed Rabbani,Niaz Mahmood,Ani Arakelian,Moshe Szyf

doi:10.3389/fonc.2020.01361

Ali Mehdi, Catalin Mihalcioiu + Show 6 more

Open Access

https://doi.org/10.3389/fonc.2020.01361

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Abstract

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.

Highlights

Melanoma has one of the top 10 incidence rates among tumor types, causing high rates of mortality and warranting an urgent need for the development of new innovative therapeutic strategies, for patients with advanced melanoma for whom treatment options are very limited [1].Epigenetic deregulation of gene transcription via DNA methylation, histone modification, and non-coding RNA is a common heritable mechanism in many cancers, including melanoma, which can alter the expression of key genes implicated in tumor progression [2]
It is established that the major anticancer effects of blockage of the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway are related to enhancing immunity against cancer, there are various reports that PDL1 triggers intrinsic signaling independent of the immune checkpoint, which promotes tumorigenesis [37, 38]
Despite melanoma being the solid tumor type most responsive to the anti-PD-1 monoclonal antibody, overall response rates are estimated around 30–33%, indicating that a considerable number of patients do not experience a reduction in tumor burden, resulting in high morbidity and mortality [1, 18, 20,21,22]

Summary

Introduction

Melanoma has one of the top 10 incidence rates among tumor types, causing high rates of mortality and warranting an urgent need for the development of new innovative therapeutic strategies, for patients with advanced melanoma for whom treatment options are very limited [1].Epigenetic deregulation of gene transcription via DNA methylation, histone modification, and non-coding RNA is a common heritable mechanism in many cancers, including melanoma, which can alter the expression of key genes implicated in tumor progression [2]. SAM effectively reduces cancer proliferation and metastasis by inhibiting angiogenesis, reducing inflammation, and downregulating several genes involved in promoting cell proliferation, invasion, and metastasis [5,6,7,8,9,10,11,12]. We reported that the antimetastatic activity of SAM in breast and prostate cancer is likely due to downregulation of prometastatic genes, such as urokinase plasminogen activator (uPA) and Matrix metallopeptidase 2 (MMP2) [6, 9]. It is unknown whether SAM has similar effects on melanoma. The role of SAM in cancer immunity has not been yet examined

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