Background: Immune checkpoint inhibitor (ICI) therapy is increasingly used for the treatment of advanced cancer, but leads to diverse cardiovascular side effects including myocarditis, left ventricular dysfunction, arrhythmia, and coronary artery disease. A disruption of cardiac immunity, characterized by increased myocardial immune cells and elevated markers for inflammation, is proposed as to trigger manifest cardiovascular toxicities. Considering the potential impact on morbidity and mortality, strategies to prevent ICI-related cardiotoxicity are urgently needed, but established immunosuppressive measures prevent the anti-tumour effect of the ICI therapy, thereby limiting its applicability to severe, life-threatening cases. Tumour necrosis factor alpha (TNFα) blockade was shown to prevent ICI-related gut toxicity while preserving, or even enhancing, anti-tumour efficacy. This study aims to investigate a cardioprotective effect of TNFα blockade during anti programmed death 1 (PD1) ICI therapy in a preclinical model as a basis for a potential new, preventive therapeutic approach for ICI-related cardiotoxicity.

Methods: Left ventricular dysfunction was induced in the CM melanoma mouse model by exposure to anti-PD1 ICI therapy for 15 days. Response to therapy was monitored by assessment of tumour size. Cardiotoxicity was confirmed by mouse echocardiography. Mice were then simultaneously treated with anti-PD1 antibodies and TNFα-blocking antibodies. A cardioprotective effect was evaluated by echocardiography and flow cytometry was used to characterize myocardial immune cells.

Results: Melanoma-bearing mice showed a profound response to anti-PD1 ICI therapy, indicated by decreased tumour size and T cell infiltration compared to control littermates as a sign for a profound response to therapy. The development of left ventricular dysfunction was confirmed by echocardiography. Mice receiving anti-PD1 ICI therapy showed 2-fold elevated concentrations of CD4⁺ and CD8⁺ T-lymphocytes in the murine heart as determined by flow cytometry. CD44 expression was upregulated in cytotoxic T-cells as a marker of enhanced T-cell activity in anti-PD1 treated mice. Administration of TNFα-blocking antibodies did not alter tumour sizes during anti-PD1 treatment as a sign for a sustained response to therapy. Remarkably, mice receiving TNFα-blocking antibodies together with anti-PD1 ICI therapy showed increased left ventricular function compared to mice receiving anti-PD1 monotherapy. As a potential mediator, cardiac T cells showed an increased expression of T cell exhaustion markers, shown in flow cytometry.

Conclusions: TNFα blockade prevented the development of left ventricular dysfunction from ICI therapy while preserving the anti-cancer efficacy. Hence, it may serve as a novel targeted cardioprotective treatment in the growing group of affected patients. Prospective studies are needed to further characterize ICI-related cardiotoxicity in patients and to evaluate the cardioprotective effects of TNFα blockade.