Abstract：
OBJECTIVE: The widespread use of immune checkpoint inhibitors (ICIs) has demonstrated significant survival benefits for cancer patients and also carry the risk of immune-related adverse events (irAEs). ICIs-associated myocarditis is a rare and serious adverse event with a high mortality rate. Here, we explored the mechanism underlying ICIs-associated myocarditis.
RESULTS: Using the peripheral blood of patients with ICIs therapy and ICIs treated mice with transplanted tumors, we dissect the immune cell subsets and inflammatory factors associated with myocarditis. Compared to the control group, patients with myocarditis after ICIs therapy showed an increase in NK cells and myeloid cells in 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-Seq revealed that CD4+ TCM cells in myocarditis patients were an immunosuppressive cell subset, which highly express the immunosuppressive factor IL4I1. 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 tumor model indicated a reduction in CD4+ TCM cells and an increase in CD8+ 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.
CONCLUSIONS: Our data highlight CD4+ TCM cells as a crucial role in cardiac protection during ICIs therapy. IL-15, IL4I1 and CD4+ TCM cells can serve as therapeutic targets to reduce ICIs-associated myocarditis in cancer patients.
RESULTS: Using the peripheral blood of patients with ICIs therapy and ICIs treated mice with transplanted tumors, we dissect the immune cell subsets and inflammatory factors associated with myocarditis. Compared to the control group, patients with myocarditis after ICIs therapy showed an increase in NK cells and myeloid cells in 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-Seq revealed that CD4+ TCM cells in myocarditis patients were an immunosuppressive cell subset, which highly express the immunosuppressive factor IL4I1. 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 tumor model indicated a reduction in CD4+ TCM cells and an increase in CD8+ 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.
CONCLUSIONS: Our data highlight CD4+ TCM cells as a crucial role in cardiac protection during ICIs therapy. IL-15, IL4I1 and CD4+ TCM cells can serve as therapeutic targets to reduce ICIs-associated myocarditis in cancer patients.
摘要：
目的：免疫检查点抑制剂（ICIs）的广泛使用已证明对癌症患者具有显着的生存益处，并且还具有免疫相关不良事件（irAE）的风险。ICIs相关心肌炎是一种罕见且严重的不良事件，死亡率高。这里,我们探讨了ICIs相关性心肌炎的潜在机制.
结果：使用ICIs治疗的患者和ICIs治疗的移植瘤小鼠的外周血，我们剖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,ICIs治疗后心肌炎患者外周血中NK细胞和骨髓细胞增加，而T细胞显著下降。在T细胞中，心肌炎患者外周血CD4/CD8比值失衡,中枢记忆CD4+T(CD4+TCM)细胞显著减少。RNA-Seq显示，心肌炎患者的CD4+TCM细胞是免疫抑制细胞亚群，高表达免疫抑制因子IL4I1。为了阐明CD4+TCM细胞减少的潜在机制，蛋白质阵列显示,随着心肌炎组心肌炎严重程度的增加,如IL-1B/CXCL13/CXCL9,而心肌保护因子IL-15降低。相关性分析显示IL-15与CD4+中药细胞呈正相关,IL-15受体IL15RA高表达。此外，在小鼠肿瘤模型中使用抗PDL1抗体的体内研究表明，CD4+TCM细胞减少，CD8+TEMRA细胞增加，还有心脏纤维化的证据.相反，抗PDL1抗体治疗与IL-15联合导致CD4+TCM细胞复活，CD8+TEMRA细胞减少，和降低心脏纤维化的风险。
结论：我们的数据强调了CD4+TCM细胞在ICIs治疗期间在心脏保护中的关键作用。IL-15、IL4I1和CD4+TCM细胞可作为降低癌症患者ICIs相关性心肌炎的治疗靶点。
结果：使用ICIs治疗的患者和ICIs治疗的移植瘤小鼠的外周血，我们剖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,ICIs治疗后心肌炎患者外周血中NK细胞和骨髓细胞增加，而T细胞显著下降。在T细胞中，心肌炎患者外周血CD4/CD8比值失衡,中枢记忆CD4+T(CD4+TCM)细胞显著减少。RNA-Seq显示，心肌炎患者的CD4+TCM细胞是免疫抑制细胞亚群，高表达免疫抑制因子IL4I1。为了阐明CD4+TCM细胞减少的潜在机制，蛋白质阵列显示,随着心肌炎组心肌炎严重程度的增加,如IL-1B/CXCL13/CXCL9,而心肌保护因子IL-15降低。相关性分析显示IL-15与CD4+中药细胞呈正相关,IL-15受体IL15RA高表达。此外，在小鼠肿瘤模型中使用抗PDL1抗体的体内研究表明，CD4+TCM细胞减少，CD8+TEMRA细胞增加，还有心脏纤维化的证据.相反，抗PDL1抗体治疗与IL-15联合导致CD4+TCM细胞复活，CD8+TEMRA细胞减少，和降低心脏纤维化的风险。
结论：我们的数据强调了CD4+TCM细胞在ICIs治疗期间在心脏保护中的关键作用。IL-15、IL4I1和CD4+TCM细胞可作为降低癌症患者ICIs相关性心肌炎的治疗靶点。
