A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety

Abstract

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block CTLA-4, PD-1, or PD-L1 and induce the activation of the immune system against cancer. Despite the efficacy of ICIs, which has improved the oncotherapy for patients with a variety of malignancies, several immune-related adverse events (irAEs) have been described, including those affecting the heart. Cardiac irAEs after ICI therapies, including myocarditis, can become life-threatening, and their pathogenic mechanisms remain unclear. Here, a systematic analysis was performed regarding the potential immune mechanisms underlying cardiac irAEs based on the immune adverse events induced by the ICIs: 1) recruitment of CD4⁺ and CD8⁺ T cells, 2) autoantibody-mediated cardiotoxicity, and 3) inflammatory cytokines. Furthermore, the impact of dual therapies in ICI-induced cardiac irAEs and the potential risk factors are reviewed. We propose that self-antigens released from cardiac tissues or cancer cells and the severity/advancement of cancer disease have an important role in ICI cardiotoxicity.

Keywords: CTLA-4; PD-1; cardiotoxicity; immune checkpoint inhibitors; myocarditis.

FIGURE 1

Proposed mechanisms of ICI-related cardiac irAEs. (A) Cardiac antigens are released by injury or stress (Nirschl and Drake, 2013). T-cell inhibition by the co-inhibitory molecules CTLA-4, PD-1, PD-L1 (Drugs@FDA, 2021). ICIs block the co-inhibitory molecules on T-cell or APC and induce anti-tumor effects (Drugs@FDA, 2021) or, in some cases, heart damage (Dyck and Mills, 2017). (B) Mechanisms of autoantibodies mediated cardiac irAEs after ICI therapies. Tumoral (Nirschl and Drake, 2013) and cardiac (Drugs@FDA, 2021) auto-antigens might be released by dying cells and damaged tissue in response to chemotherapy, radiotherapy, or resection and be recognized by autoreactive B cells. B cells cannot be activated in the absence of an inflammatory milieu and become non-viable. (Dyck and Mills, 2017). However, ICI therapies promote a chronic proinflammatory milieu allowing autoreactive B-cell activation to produce autoantibodies (Vaddepally et al., 2020). The PD-L1 expression has been reported in cardiomyocytes in the heart; therefore, anti-PD-L1-mediated CDC or ADCC may be directed to the heart inducing cardiac irAEs (Khoja et al., 2017). Striational antibodies might form an immune complex and CDC (Picardo et al., 2019). Finally, autoantibodies can directly recognize their antigen on the cardiomyocyte’s surface, induce ADCC (Haanen and Robert, 2015), or promote an agonist/antagonist response (Rubio‐Infante et al., 2021). AChR: acetylcholine receptor; ADCC: antibody-dependent cellular cytotoxicity; APC: antigen-presenting cell; C1q: complement component 1q; CD: Cluster of differentiationCD4+: T helper cell; CD8+: T cytotoxic cell; CDC: complement-dependent cytotoxicity; CTLA-4: cytotoxic T-lymphocyte-associated antigen 4; FcγR: Fc gamma receptors; Kv1.4: potassium voltage-gated channel; M2: muscarinic acetylcholine receptor 2; PD-1: programmed death 1; PD-L1: programmed death-ligand 1; RyR: ryanodine receptor. Created with BioRender.com.