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

doi:10.3389/fonc.2020.01361

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

Front Oncol. 2020 Sep 2:10:1361. doi: 10.3389/fonc.2020.01361. eCollection 2020.

Authors

Ali Mehdi^{1

2

3}, Mikhael Attias^{1

4}, Niaz Mahmood^{1

3

5}, Ani Arakelian^{1

3}, Catalin Mihalcioiu⁶, Ciriaco A Piccirillo^{1

4

5

7

8}, Moshe Szyf⁹, Shafaat Ahmed Rabbani^{1

2

3

5

6}

Affiliations

¹ Department of Medicine, McGill University, Montreal, QC, Canada.
² Human Genetics, McGill University, Montreal, QC, Canada.
³ Program in Metabolic Disorders and Complications (MeDiC), Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
⁴ Microbiology & Immunology, McGill University, Montreal, QC, Canada.
⁵ Experimental Medicine, McGill University, Montreal, QC, Canada.
⁶ Department of Oncology, McGill University, Montreal, QC, Canada.
⁷ Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
⁸ Centre of Excellence in Translational Immunology (CETI), Montreal, QC, Canada.
⁹ Department of Pharmacology, McGill University, Montreal, QC, Canada.

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.

Keywords: DNA methylation; S-adenosylmethionine; anti-PD-1; immune checkpoint inhibitors; immunity; melanoma.