Exacerbation of autoimmune myocarditis by an immune checkpoint inhibitor is dependent on its time of administration in mice

Highlights

• We developed a mouse experimental autoimmune myocarditis (EAM) model.

• Exacerbation of autoimmune myocarditis by an immune checkpoint inhibitor (ICI) is dependent on its time of administration.

• The appearance of ICI-induced autoimmune myocarditis is related to autoimmune system activity before ICI administration.

• We propose that ICI administration should be avoided in patients with autoimmune disorders.

Abstract

Background

Although immune checkpoint inhibitors (ICIs) have made an immense breakthrough in cancer therapeutics, they can exert unique, immune-related adverse events. Among them, myocarditis is less frequent, but it is serious and often follows a lethal course.

Methods

To examine the changes in cardiac autoimmunity after ICI administration, we developed a mouse experimental autoimmune myocarditis (EAM) model via intraperitoneal administration of murine α-cardiac myosin heavy chain (MyHC-α) fragment. Thereafter, the mouse anti-PD-1 antibody (mPD1ab) was administered at two time points, subsequent to and concurrent with MyHC-α fragment administration.

Results

Severe EAM developed in 3 weeks; wide inflammatory lesions were observed in the cardiac sections. Furthermore, inflammatory/fibrotic genes, such as interleukin 1β, interleukin 6, and collagen 1, were upregulated, although the cardiac function was not significantly affected. The subsequent administration of mPD1ab at 2 weeks post administration of the first MyHC-α fragment exacerbated EAM, whereas the administration of mPD1ab concurrent with MyHC-α fragment administration did not exacerbate EAM. The subsequent administration of mPD1ab significantly increased the infiltration of cluster of differentiation (CD)4- and F4/80-positive cells, whereas the concurrent administration of mPD1ab significantly decreased the infiltration of CD4-positive cells, indicating that the concurrent and subsequent administration of mPD1ab had opposite effects on immune/inflammatory cell infiltration.

Conclusions

These data suggest that the appearance of ICI-induced autoimmune myocarditis might be related to autoimmune system activity before ICI administration. Although ICIs do not adversely affect patients with normal immune systems, we propose that ICI administration should be avoided in patients with autoimmune disorders.

Introduction

Programmed cell death-1 (PD-1) is expressed on the surface of T cells, and it functions to regulate excessive autoimmune responses [1]. Programmed death-ligand 1 (PD-L1), an immune-modulating ligand of PD-1, is expressed on antigen-presenting cells and tumor cells. Immune checkpoint inhibitors (ICIs), anti-PD1 and anti-PDL1 antibodies, interrupt the interaction between PD-1 and PD-L1, thereby blocking inhibitory signals from the ligand, prolonging the activation of T cells, and in turn, inducing T cells to attack cancer cells [2]. Currently ICIs are approved to treat several carcinomas, including malignant melanoma and lung cancer [[3], [4], [5]]. Moreover, the effectiveness of combination therapy with conventional cytotoxic anticancer drugs and combination therapy of multiple ICIs has been confirmed, and the therapy using ICIs is expected to be considerably more active in the future [[6], [7], [8], [9]].

However, ICIs are known to have unique adverse effects, called immune-related adverse events (irAE), which appear in all organs of the body [10,11]. Among them, myocarditis is less frequent, but it is serious and often follows a lethal course [12]. Several reports indicate that the PD-1/PD-L1 pathway participates in maintaining peripheral tolerance to cardiac antigens. For example, a severe lethal myocarditis was reported to occur in PD-1-deficient mice, and it is characterized by considerable infiltration of CD4+ and CD8+ T cells and anti-myosin autoantibodies [13]. These studies suggest that the immune checkpoint process is closely related to the severity of myocarditis.

To study the immune events of cardiac autoimmunity, rodent models of experimental autoimmune myocarditis (EAM) are commonly employed [[14], [15], [16], [17], [18], [19]]. The disease is induced by immunizing the animals with immunodominant epitopes of cardiac antigens in complete Freund's adjuvant. The mouse EAM is a T-cell mediated disease, characterized by the infiltration of T cells and macrophages, leading to massive myocardial necrosis, which later develops into dilated cardiomyopathy in the chronic phase. However, the effect of ICIs in this EAM mouse model has not been investigated.

To the best of our knowledge, we are the first to report the effect of an anti-mouse PD-1 antibody (mPD1ab) on the development of myocarditis in this EAM model. In this study, we demonstrate that the timing of mPD1ab administration is important when determining the severity of EAM. In addition to a detailed analysis of our study's results, we have discussed the clinical adaptation of ICI therapy below.