46P - Abnormal gut microbiota may cause PD-1 inhibitor-related cardiotoxicity via suppressing regulatory T cells

Background

The mechanism of PD-1 inhibitors-induced myocarditis in individuals with tumor is still unclear. Regulatory T cells (Treg) can directly inhibit T cell proliferation and activation, and also produce inhibitory cytokines with potent immunosuppressive properties. Deletion or aberrant function of Treg usually leads to autoimmune diseases. But reports on the role of Treg in PD-1 inhibitor-associated myocarditis are still very limited, and its role in the pathogenesis of myocarditis needs to be further explored. In addition, alterations in the composition of the gut microbiota and its metabolites have been shown to be involved in the development of several cardiovascular and autoimmune diseases.

Methods

We first established a melanoma model in mice, which were subsequently divided into three groups: control group, Anti-PD1 group and fecal microbiota removal (FMR) group. The control group and Anti-PD1 group were subcutaneously injected with mouse IgG and PD-1 inhibitors respectively, and FMR group were injected with PD-1 inhibitors subcutaneously along with oral antibiotic antimicrobials to clear the intestinal microbiota. Afterwards, we assessed the severity of myocarditis in mice, performed flow cytometry analysis of immune cells in the heart, determined transcript levels of Treg-related cytokines in the heart, and performed 16S rRNA gene sequence analysis of gut microbiota and correlation analysis of enriched gut microbiota with myocarditis factors.

Results

PD-1 inhibitors induced myocarditis in melanoma mice, leading to a reduction in intracardiac Tregs and downregulation of inflammatory suppressor transcript levels, as well as altering the gut microbial composition of the mice. However, in the presence of gut microbial removal, myocarditis manifestations in the mice described above were attenuated. In addition, microbes enriched in the gut of mice after treatment with PD-1 inhibitors showed a strong correlation with factors associated with the development of myocarditis.

Conclusions

PD-1 inhibitors induced myocarditis and significant reduction of intracardiac Treg in melanoma mice. It is highly likely that alterations in the composition of the gut microbiota due to PD-1 inhibitors played a key role in this process.

Legal entity responsible for the study

The authors.

Funding

Shanxi Provincial Health Commission.

Disclosure

All authors have declared no conflicts of interest.