TY - JOUR
T1 - Evidences of CTLA-4 and PD-1 blocking agents-induced cardiotoxicity in cellular and preclinical models
AU - Quagliariello, Vincenzo
AU - Passariello, Margherita
AU - Rea, Domenica
AU - Barbieri, Antonio
AU - Iovine, Martina
AU - Bonelli, Annamaria
AU - Caronna, Antonietta
AU - Botti, Gerardo
AU - De Lorenzo, Claudia
AU - Maurea, Nicola
N1 - Funding Information:
Funding: This work was funded by a “Ricerca Corrente” grant from the Italian Ministry of Health. “Cardiotossicità dei trattamenti antineoplastici: identificazione precoce e strategie di cardioprotezione” Project code: M1/5-C.
Publisher Copyright:
© 2020 by the authors.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - 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-κB 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-κB, 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-κB 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.
AB - 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-κB 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-κB, 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-κB 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.
KW - Cardioncology
KW - Cardiotoxicity
KW - Immune checkpoint inhibitors
KW - Ipilimumab
KW - Nivolumab
UR - http://www.scopus.com/inward/record.url?scp=85094194377&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85094194377&partnerID=8YFLogxK
U2 - 10.3390/jpm10040179
DO - 10.3390/jpm10040179
M3 - Article
AN - SCOPUS:85094194377
VL - 10
SP - 1
EP - 19
JO - Journal of Personalized Medicine
JF - Journal of Personalized Medicine
SN - 2075-4426
IS - 4
M1 - 179
ER -