Ipilimumab and Nivolumab exerted significant cardiotoxic effects in cellular and murine models, mediated by the NLRP3/IL-1β and MyD88 pathways, leading to a pro-inflammatory cytokine storm.
Do ipilimumab and nivolumab induce cardiotoxicity through pro-inflammatory pathways in cellular and murine models?
Nivolumab and ipilimumab exert cardiotoxic effects mediated by NLRP3/IL-1β and MyD88 pathways, leading to a pro-inflammatory cytokine storm and reduced cardiac function in preclinical models.
BACKGROUND: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed for cancer therapy, opening to advantages in cancer outcomes. However, several ICI-induced side effects have emerged in these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. We studied the cytotoxic and pro-inflammatory properties of Ipilimumab and Nivolumab, the underlying pathways and cytokine storm involved. METHODS: Co-cultures of human cardiomyocytes and lymphocytes were exposed to Ipilimumab or Nivolumab; cell viability and expression of leukotrienes, NLRP3, MyD88, and p65/NF-kB were performed. C57 mice were treated with Ipilimumab (15 mg/kg); analysis of fractional shortening, ejection fraction, radial and longitudinal strain were made before and after treatments through 2D-echocardiography. Expression of NLRP3, MyD88, p65/NF-kB, and 12 cytokines were analyzed in murine myocardium. RESULTS: Nivolumab and Ipilimumab exert effective anticancer, but also significant cardiotoxic effects in co-cultures of lymphocytes and tumor or cardiac cells. Both ICIs increased NLRP3, MyD88, and p65/NF-kB expression compared to untreated cells, however, the most pro-inflammatory and cardiotoxic effects were seen after exposure to Ipilimumab. Mice treated with Ipilimumab showed a significant decrease in fractional shortening and radial strain with respect to untreated mice, coupled with a significant increase in myocardial expression of NLRP3, MyD88, and several interleukins. CONCLUSIONS: Nivolumab and Ipilimumab exert cytotoxic effects mediated by the NLRP3/IL-1β and MyD88 pathways, leading to pro-inflammatory cytokine storm in heart tissue.
Quagliariello et al. (Mon,) conducted a other in ICI-induced cardiotoxicity. Ipilimumab and Nivolumab vs. Untreated cells and mice was evaluated on Cytotoxic and pro-inflammatory properties, fractional shortening, and myocardial strain. Ipilimumab and Nivolumab exerted significant cardiotoxic effects in cellular and murine models, mediated by the NLRP3/IL-1β and MyD88 pathways, leading to a pro-inflammatory cytokine storm.