Programmed Cell Death-1: Programmed Cell Death-Ligand 1 Interaction Protects Human Cardiomyocytes Against T-Cell Mediated Inflammation and Apoptosis Response In Vitro

Abstract

Aim: Immunological checkpoint therapy is considered a powerful method for cancer therapy and acts by re-activating autologous T cells to kill the cancer cell. Myocarditis cases have been reported in cancer patients after immunological therapy; for example, nivolumab treatment is a monoclonal antibody that blocks programmed cell death-1/programmed cell death ligand-1 ligand interaction. This project provided insight into the inflammatory response as a benchmark to investigate the potential cardiotoxic effect of T cell response to the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis in regulating cardiomyocyte injury in vitro. Methods and Results: We investigated cardiomyopathy resulted from the PD-1/PD-L1 axis blockade using the anti-PD-1 antibody in Rockefeller University embryonic stem cells-derived cardiomyocytes (RUES2-CMs) and a melanoma tumor-bearing murine model. We found that nivolumab alone did not induce inflammatory-related proteins, including PD-L1 expression, and did not induce apoptosis, which was contrary to doxorubicin, a cardiotoxic chemotherapy drug. However, nivolumab was able to exacerbate the immune response by increasing cytokine and inflammatory gene expression in RUES2-CMs when co-cultured with CD4+ T lymphocytes and induced apoptosis. This effect was not observed when RUES2-CMs were co-cultured with CD8+ T lymphocytes. The in vivo model showed that the heart function of tumor-bearing mice was decreased after treatment with anti-PD-1 antibody and demonstrated a dilated left ventricle histological examination. The dilated left ventricle was associated with an infiltration of CD4+ and CD8+ T lymphocytes into the myocardium. PD-L1 and inflammatory-associated gene expression were significantly increased in anti-PD-1-treated tumor-bearing mice. Cleaved caspase-3 and mouse plasma cardiac troponin I expressions were increased significantly. Conclusion: PD-L1 expression on cardiomyocytes suppressed T-cell function. Blockade of PD-1 by nivolumab enhanced cardiomyocyte inflammation and apoptosis through the enhancement of T-cell response towards cardiomyocytes.

Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: A Systematic Review

“…Expression of the inflammatory transcription factors NLRP3, MyD88, and p65/NF-κB are also increased in cardiomyocytes after ICI treatment [30]. Further proving this point, anti-PD-1-treated mice had more CD4+ and CD8+ T cell infiltration in the heart as compared to a control group [29]. However, it is unclear exactly what the T cells are targeting.…”

“…Love et al found in a similar study that CTLA-4 removal on T cells also caused severe myocarditis in mice, but lack of IL-12 prevented CD8+ T cells from proliferating, thus ameliorating the myocarditis [32]. PD-L1 expressed in the human myocardium is involved in protecting immune-mediated cardiac injury and inflammation [29].…”

“…The mechanism of cardiotoxicity is still under research, but it may primarily involve CD4+ mediated T cell inflammation [28]. A study by Tay et al confirmed that nivolumab does not induce cardiomyocyte apoptosis like a cytotoxic drug such as doxorubicin does-rather, it increases pro-inflammatory cytokine production in CD4+ T cells only [29]. The most common cytokines produced include TNF-α, granzyme B, and IFN-γ [27].…”

Clinical implications of isolated troponinemia following immune checkpoint inhibitor therapy

“…The risk of cardiovascular complications seen upon PD-1/PD-L1 and combination therapy was much higher as opposed to CTLA-4 therapy. 8,53 Furthermore, Tay et al 54 provided insights into cardiomyopathy resulting from PD-1-PD-L1 axis blockade, by using nivolumab in vitro in Rockefeller University embryonic stem cells (RUES)derived cardiomyocytes and in vivo in melanoma tumorbearing mice. They observed cardiomyocyte inflammation and apoptosis along with an increased expression of cardiac TnI and left ventricular dilatation.…”

“…They observed cardiomyocyte inflammation and apoptosis along with an increased expression of cardiac TnI and left ventricular dilatation. 54 Thus, elevated troponin levels might indicate low-grade or scattered myocardial inflammation as a result of blocking the PD-1–PD-L1 axis which might not yet be visual on cardiac imaging. 55 , 56 The best technique to diagnose subclinical cardiac dysfunction has not yet been established.…”