School of Medicine, Chongqing University, Chongqing 400030, China.
Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, No. 181, Hanyulu, Shapingba, Chongqing 400030, China.
Cardiovasc Res. 2024 Oct 14;120(12):1442-1455. doi: 10.1093/cvr/cvae133.
The widespread use of immune checkpoint inhibitors (ICIs) has demonstrated significant survival benefits for cancer patients and also carries the risk of immune-related adverse events. ICI-associated myocarditis is a rare and serious adverse event with a high mortality rate. Here, we explored the mechanism underlying ICI-associated myocarditis.
Using the peripheral blood of patients with ICI therapy and of ICI-treated mice with transplanted tumours, we dissect the immune cell subsets and inflammatory factors associated with myocarditis. Compared to the control group, patients with myocarditis after ICI therapy showed an increase in NK cells and myeloid cells in the peripheral blood, while T cells significantly decreased. Among T cells, there was an imbalance of CD4/CD8 ratio in the peripheral blood of myocarditis patients, with a significant decrease in central memory CD4+ T (CD4+ TCM) cells. RNA sequencing revealed that CD4+ TCM cells in myocarditis patients were immunosuppressive cell subsets, which highly express the immunosuppressive factor IL-4I1. To elucidate the potential mechanism of the decrease in CD4+ TCM cells, protein array was performed and revealed that several inflammatory factors gradually increased with the severity of myocarditis in the myocarditis group, such as IL-1B/CXCL13/CXCL9, while the myocardial protective factor IL-15 decreased. Correlation analysis indicated a positive correlation between IL-15 and CD4+ TCM cells, with high expression of IL-15 receptor IL15RA. Furthermore, in vivo studies using an anti-PDL1 antibody in a mouse tumour model indicated a reduction in CD4+ TCM cells and an increase in effector memory-expressing CD45RA CD8+ T (TEMRA) cells, alongside evidence of cardiac fibrosis. Conversely, combining anti-PDL1 antibody treatment with IL-15 led to a resurgence of CD4+ TCM cells, a reduction in CD8+ TEMRA cells, and a mitigated risk of cardiac fibrosis.
Our data highlight CD4+ TCM cells' crucial role in cardiac protection during ICI therapy. IL-15, IL-4I1, and CD4+ TCM cells can serve as therapeutic targets to reduce ICI-associated myocarditis in cancer patients.
免疫检查点抑制剂（ICI）的广泛应用为癌症患者带来了显著的生存获益，但也存在免疫相关不良反应的风险。ICI 相关性心肌炎是一种罕见且严重的不良反应，死亡率较高。本研究旨在探讨 ICI 相关性心肌炎的发病机制。
利用接受 ICI 治疗的患者和接受 ICI 治疗的荷瘤小鼠的外周血，我们解析了与心肌炎相关的免疫细胞亚群和炎症因子。与对照组相比，ICI 治疗后发生心肌炎的患者外周血中 NK 细胞和髓系细胞增加，而 T 细胞明显减少。在 T 细胞中，心肌炎患者外周血中 CD4/CD8 比值失衡，中央记忆性 CD4+T（CD4+TCM）细胞显著减少。RNA 测序显示，心肌炎患者的 CD4+TCM 细胞为免疫抑制性细胞亚群，高表达免疫抑制因子 IL-4I1。为了阐明 CD4+TCM 细胞减少的潜在机制，我们进行了蛋白质谱分析，结果显示，在心肌炎组中，随着心肌炎严重程度的增加，几种炎症因子（如 IL-1B/CXCL13/CXCL9）逐渐增加，而心肌保护因子 IL-15 减少。相关性分析表明，IL-15 与 CD4+TCM 细胞呈正相关，IL-15 受体 IL15RA 高表达。此外，在小鼠肿瘤模型中使用抗 PD-L1 抗体进行的体内研究表明，CD4+TCM 细胞减少，表达效应记忆的 CD45RA CD8+T（TEMRA）细胞增加，同时伴有心肌纤维化的证据。相反，将抗 PD-L1 抗体治疗与 IL-15 联合使用可使 CD4+TCM 细胞重新出现，减少 CD8+TEMRA 细胞，并降低心脏纤维化的风险。
我们的数据强调了 CD4+TCM 细胞在 ICI 治疗期间心脏保护中的关键作用。IL-15、IL-4I1 和 CD4+TCM 细胞可作为治疗靶点，以减少癌症患者的 ICI 相关性心肌炎。
