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

Abstract

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.

Comparative Transcriptomics of Immune Checkpoint Inhibitor Myocarditis Identifies Guanylate Binding Protein 5 and 6 Dysregulation

“…In another study, a combination of coxsackievirus B3 infection and PD-1/PD-L1 inhibitors induced acute myocarditis [20]. Another two studies in which C57/Bl6 mice were treated with PD-1 inhibitors [21] or CTLA-4 inhibitors [22] describe a deterioration in left ventricular function in response to the blockage of the immune checkpoints.…”

SARS-CoV-2 Infection and Cardioncology: From Cardiometabolic Risk Factors to Outcomes in Cancer Patients

“…ICIs activate the immune response through the inhibition of CTLA-4, PD-1, or PDL-1-related pathways; outcomes in cancer patients are well documented with improved survival in patients with several cancers [ 52 ]. However, a broad spectrum of side effects has been recorded, involving vasculitis, venous thromboembolism, Takotsubo syndrome, atherosclerosis, myocarditis, and hypertension [ 54 , 55 ]. Actually, many discussions are open about the beneficial or harmful role of ICIs in patients with COVID-19 [ 51 ].…”

“…Known risk factors for viral myocarditis are high age, malnutrition (i.e., vitamin E and selenium deficiency as well as exposure to high doses of mercury), and sex hormones [ 59 , 60 ]. The pathogenesis of viral-induced myocarditis involves both innate and acquired immune response in myocardium: the innate immune response involves the release of nitric oxide and cytokines production (tumour necrosis factor, interferones, interleukins); the acquired immune response is based on the infiltration of monocytes, macrophages, B and T lymphocytes, antibodies, and autoantibodies [ 61 ] against cardiomyocytes [ 54 , 59 ]. Several studies associated COVID-19 to a high risk of fatal myocarditis, both in adults and children patients [ 8 ].…”

“…The pathogenesis of myocarditis and COVID-19 involves the same interleukins and cytokines [ 65 ]; in fact, the ICU COVID-19 patients described in the literature have high plasma cytokines that induced the recruitment of immune cells in the myocardium [ 59 ]. Fatal myocarditis is well known in oncology, considering that some anticancer drugs are well associated to innate or acquired immune response in myocardial tissues, as described in Section 3 [ 54 , 55 ]. Notably, myocarditis has a prevalence of 0.06% and 2.4% in cancer patients treated with ICIs, especially when combined [ 66 ].…”

The Mechanism and Management of Adverse Cardiac Reactions Induced by Immune Checkpoint Inhibitors Therapy

“…They analyzed changes in fractional shortening, ejection fraction, and radial and longitudinal strain before and after treatments through 2D-echocardiography. Meanwhile, the expressions of NLRP3, MyD88, p65/NF-kB, and 12 cytokines were analyzed in murine myocardium [ 23 ]. This indicates that ICIs may induce proinflammatory cytokine storms in heart tissue through the cytotoxic effects mediated by NLRP3/IL-1 β and MyD88 pathways.…”