Pembrolizumab, Ipilimumab and Nivolumab reduces cardiac pAMPK and IL-10, increases vascular NF-kB expression and levels of IL-1b, IL-2 and IL-6 in myocardial tissue

Abstract Background Several strategies based on immune checkpoint inhibitors (ICIs) have been developed or are under investigation for cancer therapy, opening to advantages in cancer outcomes. However, several ICIs-induced side effects emerged in these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. Purpose We analyzed the differential vasculo and cardiotoxicity of Pembrolizumab, Nivolumab and Ipilimumab in preclinical models highlighting on the molecular pathways involved. Methods C57 female mice were treated with Ipilimumab, Pembrolizumab or Nivolumab (15 mg/kg) through intraperitoneal injection for 10 days. pAMPK expression and vascular p65/NF-kB was analyzed through Immunohistochemistry. Cardiac levels of IL-1α, IL-1β, IL-2, IL-6 and IL-10 were quantified through ELISA method Results In preclinical models, all ICIs increased p65/NF-kB expression in vascular endothelial cells of mice compared to saline group. IHC analysis indicates that ICIs reduced pAMPK expression in myocardial cells. Notably, tissue levels of IL-1α, IL-1β, IL-2, IL-6 were strongly increased in ICIs group vs saline (p<0.05 vs saline). On the other hand, levels of the anti-inflammatory cytokine IL-10 were strongly reduced (overall reduction of 43.3–54.5% vs saline) Conclusion In preclinical models, a short treatment with ICIs is sufficient to confer a pro-inflammatory phenotype in the heart of mice. Furthermore, reductions in pAMPK indicate the inhibition of mitochondrial metabolism after ICIs. Furthermore ICIs induce chemokines involved in fibrosis, myocarditis and vascultitis. These results could indicate new therapeutic candidates aimed to prevent myocardial and vascular damages in cancer patients treated with ICIs. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Ricerca Corrente, Ministero della Salute