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

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.

Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers

“…Indeed, in preclinical models, the N1-acetylspermidine precursor, spermidine, has marked anti-inflammatory and immunostimulatory effects 24 – 27 . Administration of S-adenosylmethionine attenuates the cytokine storm induced by bacterial sepsis 28 and mediates immunostimulatory effects in a cancer model 29 . Clinical trials have demonstrated that taurine, the downstream metabolite of hypotaurine, decreases serum markers of inflammation including C-reactive protein 30 , which is a negative prognostic marker of COVID-19 31 .…”

Role of Methylation in Pro- and Anti-Cancer Immunity

“…This makes CD8+ T cells non-functional and unresponsive to ICPi [ 175 ]. Indeed, we showed that SAM in combination with ICPi (anti-PD-1) significantly reduced tumor volume and weight compared to monotherapy in a syngeneic mouse model of advanced melanoma [ 177 ]. This effect was partially due to the elevated activation, proliferation, and cytokine production of CD8 T cells.…”

Targeting STAT3 Abrogates Tim-3 Upregulation of Adaptive Resistance to PD-1 Blockade on Regulatory T Cells of Melanoma

“…In our study, there was no observed synergistic effect between STAT3 inhibitor Stattic and anti-PD-1. Former research showed that the effect of combination treatment containing anti-PD-1 therapy on melanoma was not significant in the short term when compared to anti-PD-1 alone after tumor formation for 14 days (46). Another study focused on the antitumor activity of combinations of cytotoxic chemotherapy and immune checkpoint inhibitors of various mouse models.…”