Fu Jiding, Wang Ge, Zeng Lisi, Lin Jie, Wei Yier, Xu Wei, Xu Rui, Xian Lewu
Department of Intensive Care Unit, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China.
Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China.
Cent Eur J Immunol. 2025;50(1):24-37. doi: 10.5114/ceji.2025.149377. Epub 2025 Apr 9.
Cardiotoxicity caused by immune checkpoint inhibitors is one of the most severe and potentially fatal side effects. Hence it is crucial from a therapeutic standpoint to understand the underlying processes and devise countermeasures. This study sought to determine whether the SOCS3/JAK/STAT3 signaling pathway, which controls macrophage polarization, contributes to the cardiotoxicity caused by PD-1/PD-L1 inhibitors. The PD-1/PD-L1 inhibitor BMS-1 (10 mg/kg) was used to create a mouse model of immune checkpoint inhibitor-related cardiotoxicity, and hematoxylin and Masson's trichome tests were used to measure cardiomyocyte apoptosis and cardiotoxicity. The production of M1 factors (tumor necrosis factor [TNF-] and interleukin [IL]-1 ), as well as the blood levels of myocardial enzymes (creatine kinase, aspartate transaminase, creatine kinase-MB, and lactate dehydrogenase), were evaluated by ELISA. Echocardiography was used to assess the heart's health. The processes were investigated using flow cytometric analysis, real-time PCR, Western blot, and chromatin immunoprecipitation. We found that the PD-1/PD-L1 inhibitor BMS-1 dramatically reduced tumor weight while considerably impairing cardiac function in melanoma-induced tumor-bearing mice. At the gene and protein levels, it was found that levels of SOCS3, JAK, STAT3, and the inflammatory mediators IL-6 and TNF- had all significantly decreased. Immune checkpoint inhibitor-induced cardiotoxicity may be linked to major changes in the SOCS3/JAK/STAT3 signaling pathway, as indicated by the knockdown of SOCS3, JAK, and STAT3. Finally, immune checkpoint inhibitor intervention demonstrated a large elevation of CD86+ and MHCII+ as well as a considerable increase in macrophages. These data suggest that the SOCS3/JAK/STAT3 signaling pathway, which controls macrophage polarization, may be linked to cardiotoxicity caused by PD-1/PD-L1 inhibitor therapy.
免疫检查点抑制剂引起的心脏毒性是最严重且可能致命的副作用之一。因此，从治疗角度理解其潜在机制并制定应对措施至关重要。本研究旨在确定控制巨噬细胞极化的SOCS3/JAK/STAT3信号通路是否与PD-1/PD-L1抑制剂引起的心脏毒性有关。使用PD-1/PD-L1抑制剂BMS-1（10毫克/千克）建立免疫检查点抑制剂相关心脏毒性的小鼠模型，并用苏木精和Masson三色染色试验检测心肌细胞凋亡和心脏毒性。通过酶联免疫吸附测定法评估M1因子（肿瘤坏死因子[TNF-]和白细胞介素[IL]-1）的产生以及心肌酶（肌酸激酶、天冬氨酸转氨酶、肌酸激酶同工酶MB和乳酸脱氢酶）的血液水平。用超声心动图评估心脏健康状况。通过流式细胞术分析、实时聚合酶链反应、蛋白质印迹法和染色质免疫沉淀法对相关过程进行研究。我们发现，在黑色素瘤诱导的荷瘤小鼠中，PD-1/PD-L1抑制剂BMS-1显著降低了肿瘤重量，但同时严重损害了心脏功能。在基因和蛋白质水平上，发现SOCS3、JAK、STAT3以及炎症介质IL-6和TNF-的水平均显著下降。SOCS3、JAK和STAT3的敲低表明，免疫检查点抑制剂诱导的心脏毒性可能与SOCS3/JAK/STAT3信号通路的重大变化有关。最后，免疫检查点抑制剂干预显示CD86+和MHCII+大幅升高，巨噬细胞也显著增加。这些数据表明，控制巨噬细胞极化的SOCS3/JAK/STAT3信号通路可能与PD-1/PD-L1抑制剂治疗引起的心脏毒性有关。
