1944P Hyperglycemia increased nivolumab-induced cardiotoxicity, enhanced immunoresistance of ERɑ+, PR+, HER2- breast cancer cells modulating growth factors and NLRP3 expression

Abstract

Type 2 diabetes and metabolic syndrome are negative prognostic factors in breast cancer patients. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, achieving unprecedented efficacy in multiple malignancies. We aimed to study if hyperglycemia could enhance ICI-induced cardiotoxicity in cardiomyocites and immunoresistance in human breast cancer cells. Finally, we evaluated if the treatment with an SGLT-2 inhibitor (empagliflozin) could revert these effects during hyperglycemic condition. Human cardiomyocytes (HL-1 cells) and PD-1+ ERɑ+, PR+, HER2- breast cancer cells (MCF-7 cell line) were exposed to nivolumab (100 nM) at high glucose (25 mM) low glucose (5.5 mM) for 72 h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity; NLRP3, p65/NF-kB and leukotrienes expression through ELISA method. Nivolumab-induced cardiotoxicity was enhanced by 2,7-fold during exposure to 25 mM glucose (High Glucose; HG) compared to 5.5 mM glucose (Low Glucose; LG) in human adult cardiomyocytes. Moreover, IC50 value of nivolumab against MCF7-cells increased significantly under HG vs LG (P<0.01). Moreover, during high glucose condition, cardiomyocytes and human breast cancer cells exposed to nivolumab, increases the expression of NLRP3, p65/NF-kB, leukotrienes and cytokines. Notably, hyperglycemia increases significantly the intracellular calcium (iCa2+) content in cardiomyocytes during incubation with nivolumab, probably increasing the metabolic susceptibility to damages induced by ICI. Shifting from HG to LG, as well as the administration of 50 nM empagliflozin reduced the magnitude of cardiotoxic effects, indicating cardioprotective and immuno-enhancing properties. To our knowledge these results are the first evidence that hyperglycemia exacerbates ICI-induced cardiotoxicity and immunoresistace and set the stage to preclinical and clinical trials aimed to decrease glucose through dietary or lifestyle changes or through new hypoglycemic drugs (gliflozins).