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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  <identifier identifierType="DOI">10.5281/zenodo.5152889</identifier>
  <creators>
    <creator>
      <creatorName>Vincenzo Quagliariello</creatorName>
      <affiliation>Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale</affiliation>
    </creator>
    <creator>
      <creatorName>Margherita Passariello</creatorName>
      <affiliation>CEINGE—Biotecnologie Avanzate s.c.a.r.l.,</affiliation>
    </creator>
    <creator>
      <creatorName>Domenica Rea</creatorName>
      <affiliation>Animal Facility, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale</affiliation>
    </creator>
    <creator>
      <creatorName>Antonio Barbieri</creatorName>
      <affiliation>Animal Facility, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale</affiliation>
    </creator>
    <creator>
      <creatorName>Martina Iovine</creatorName>
      <affiliation>Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale</affiliation>
    </creator>
    <creator>
      <creatorName>Annamaria Bonelli</creatorName>
      <affiliation>Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale</affiliation>
    </creator>
    <creator>
      <creatorName>Antonietta Caronna</creatorName>
      <affiliation>Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale</affiliation>
    </creator>
    <creator>
      <creatorName>Gerardo Botti</creatorName>
      <affiliation>Scientific Direction, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale</affiliation>
    </creator>
    <creator>
      <creatorName>Claudia De Lorenzo</creatorName>
      <affiliation>Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II"</affiliation>
    </creator>
    <creator>
      <creatorName>Nicola Maurea</creatorName>
      <affiliation>Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale</affiliation>
    </creator>
  </creators>
  <titles>
    <title>Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models</title>
  </titles>
  <publisher>Zenodo</publisher>
  <publicationYear>2020</publicationYear>
  <dates>
    <date dateType="Issued">2020-10-19</date>
  </dates>
  <resourceType resourceTypeGeneral="JournalArticle"/>
  <alternateIdentifiers>
    <alternateIdentifier alternateIdentifierType="url">https://zenodo.org/record/5152889</alternateIdentifier>
  </alternateIdentifiers>
  <relatedIdentifiers>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsIdenticalTo" resourceTypeGeneral="JournalArticle">10.3390/jpm10040179</relatedIdentifier>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsVersionOf">10.5281/zenodo.5152888</relatedIdentifier>
  </relatedIdentifiers>
  <rightsList>
    <rights rightsURI="https://creativecommons.org/licenses/by/4.0/legalcode">Creative Commons Attribution 4.0 International</rights>
    <rights rightsURI="info:eu-repo/semantics/openAccess">Open Access</rights>
  </rightsList>
  <descriptions>
    <description descriptionType="Abstract">&lt;p&gt;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-1&amp;beta; and MyD88 pathways, leading to pro-inflammatory cytokine storm in heart tissue.&lt;/p&gt;</description>
  </descriptions>
</resource>
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