Lu Yang, Gao Jiamin, Hou Yachen, Yang Han, Wang Dashuai, Zhang Ge, Qin Zhen, Du Pengchong, Wang Zhenwei, Wang Yunzhe, Chen Quanzhou, Sun Zhaowei, Li Ping, Zhang Jinying, Tang Junnan
Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, China.
J Immunother Cancer. 2025 Jan 7;13(1):e010127. doi: 10.1136/jitc-2024-010127.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many malignant tumors. However, ICI-induced hyper-immune activation causes cardiotoxicity. Traditional treatments such as glucocorticoids and immunosuppressants have limited effectiveness and may even accelerate tumor growth. This study aimed to identify approaches that effectively reduce cardiotoxicity and simultaneously preserve or enhance the antitumor immunity of ICI therapy.
ICI injection in melanoma-bearing C57BL/6J female mice was used to simulate cardiotoxicity in patients with tumor undergoing immune therapy. MCC950 was used to block nod-like receptor protein 3 (NLRP3) inflammasome activity. Echocardiography, immunofluorescence, flow cytometry, and reverse transcription quantitative polymerase chain reaction were used to assess cardiac function, immune cell populations, and inflammatory factor levels. Bulk and single-cell RNA sequencing was used to detect the changes in cardiac transcriptome and immunological network.
NLRP3 inhibition reduced inflammatory response and improved cardiac function. Notably, NLRP3 inhibition also resulted in a pronounced suppression of tumor growth. Single-cell RNA sequencing elucidated that MCC950 treatment reduced the cardiac infiltration of pathogenic macrophages, cytotoxic T cells, activated T cells, and their production of inflammatory cytokines, while enhancing the presence of reparative macrophages and naive T cells. In addition, MCC950 attenuated cardiotoxicity induced by dual programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy and promoted tumor regression, and showed efficacy in treating established cardiotoxicity.
Our findings provide a promising clinical approach for preventing and treating cardiotoxicity induced by ICIs, dissociating the antitumor efficacy of ICI-based therapies from their cardiotoxic side effects.
免疫检查点抑制剂（ICI）彻底改变了许多恶性肿瘤的治疗方式。然而，ICI诱导的过度免疫激活会导致心脏毒性。传统治疗方法如糖皮质激素和免疫抑制剂效果有限，甚至可能加速肿瘤生长。本研究旨在确定能有效降低心脏毒性，同时保留或增强ICI治疗抗肿瘤免疫力的方法。
通过给荷黑色素瘤的C57BL/6J雌性小鼠注射ICI来模拟接受免疫治疗的肿瘤患者的心脏毒性。使用MCC950阻断NOD样受体蛋白3（NLRP3）炎性小体活性。采用超声心动图、免疫荧光、流式细胞术和逆转录定量聚合酶链反应来评估心脏功能、免疫细胞群体和炎症因子水平。利用批量和单细胞RNA测序检测心脏转录组和免疫网络的变化。
NLRP3抑制减少了炎症反应并改善了心脏功能。值得注意的是，NLRP3抑制还导致肿瘤生长明显受抑。单细胞RNA测序表明，MCC950治疗减少了致病性巨噬细胞、细胞毒性T细胞、活化T细胞的心脏浸润及其炎性细胞因子的产生，同时增加了修复性巨噬细胞和初始T细胞的存在。此外，MCC950减轻了双重程序性细胞死亡蛋白1（PD-1）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）免疫治疗诱导的心脏毒性，并促进肿瘤消退，且对已确立的心脏毒性具有治疗效果。
我们的研究结果为预防和治疗ICI诱导的心脏毒性提供了一种有前景的临床方法，将基于ICI的治疗的抗肿瘤疗效与其心脏毒性副作用分离。
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