Journal article Open Access

Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models

Vincenzo Quagliariello; Margherita Passariello; Domenica Rea; Antonio Barbieri; Martina Iovine; Annamaria Bonelli; Antonietta Caronna; Gerardo Botti; Claudia De Lorenzo; Nicola Maurea

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<oai_dc:dc xmlns:dc="" xmlns:oai_dc="" xmlns:xsi="" xsi:schemaLocation="">
  <dc:creator>Vincenzo Quagliariello</dc:creator>
  <dc:creator>Margherita Passariello</dc:creator>
  <dc:creator>Domenica Rea</dc:creator>
  <dc:creator>Antonio Barbieri</dc:creator>
  <dc:creator>Martina Iovine</dc:creator>
  <dc:creator>Annamaria Bonelli</dc:creator>
  <dc:creator>Antonietta Caronna</dc:creator>
  <dc:creator>Gerardo Botti</dc:creator>
  <dc:creator>Claudia De Lorenzo</dc:creator>
  <dc:creator>Nicola Maurea</dc:creator>
  <dc:description>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.</dc:description>
  <dc:title>Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models</dc:title>
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