CD24-Fc suppression of immune related adverse events in a therapeutic cancer vaccine model of murine neuroblastoma.
CD24-Fc suppression of immune related adverse events in a therapeutic cancer vaccine model of murine neuroblastoma.
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DOI：
10.3389/fimmu.2023.1176370
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发表时间：
2023
影响因子：
7.3
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中科院分区：
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myc抑制的整个肿瘤细胞与靶向CTLA-4和PD-L1的检查点抑制剂结合，在小鼠神经母细胞瘤模型中产生了一种有效的治疗性癌症疫苗。随着免疫疗法从临床前转向临床试验，与诱导强效免疫相关的潜在免疫相关不良事件（irAEs）必须得到解决。CD24-Siglec 10/G相互作用是一种先天检查点，可消除对受损细胞释放的分子的炎症反应，但其在癌症免疫学中的作用尚不明确。我们研究了一种有效的全细胞神经母细胞瘤疫苗的irae，并随后在小鼠神经母细胞瘤模型中研究了CD24-Fc（一种CD24和Fc融合蛋白）对疫苗效果和诱导的irae的影响。为了测试整个肿瘤细胞接种是否会导致其他器官系统的自身免疫反应，我们在肿瘤接种和疫苗治疗后的第30天，从naïve小鼠（n=3）、未接种肿瘤的小鼠（n=3）和接种CD24 Fc或人IgG-Fc对照的小鼠（n=12）中获取肺、心脏、肾脏和结肠。利用纳米串自身免疫谱分析技术研究了不同器官系统的免疫细胞浸润和免疫原性通路特征。免疫组织化学染色验证纳米链RNA转录结果。全肿瘤细胞疫苗与免疫检查点疗法联合可引发隐匿器官特异性免疫细胞浸润，主要在心脏组织中，在较小程度上在肾和肺组织中，但在结肠中没有。疫苗接种时给药CD24-Fc部分阻碍了抗肿瘤免疫，但首次接种后延迟给药CD24-Fc逆转了这种作用。CD24-Fc治疗还能改善由有效的肿瘤疫苗接种引起的心脏自身免疫反应。本研究表明，Myc抑制全肿瘤细胞接种与检查点抑制剂联合是一种有效的治疗方法，但在小鼠神经母细胞瘤模型中，在几个器官系统中诱导了隐性免疫浸润。全身给药CD24-Fc可抑制自身免疫组织反应，但适当的给药时间对于维持治疗性疫苗的疗效至关重要。
The combination of Myc-suppressed whole tumor cells with checkpoint inhibitors targeting CTLA-4 and PD-L1 generates a potent therapeutic cancer vaccine in a mouse neuroblastoma model. As immunotherapies translate from pre-clinical to clinical trials, the potential immune-related adverse events (irAEs) associated with induction of potent immunity must be addressed. The CD24-Siglec 10/G interaction is an innate checkpoint that abrogates inflammatory responses to molecules released by damaged cells, but its role in cancer immunology is not well defined. We investigate irAEs of an effective whole cell neuroblastoma vaccine and subsequently the effect of CD24-Fc, a CD24 and Fc fusion protein, on both the vaccine efficacy and induced irAEs in a mouse neuroblastoma model. To test whether the whole tumor cell vaccination leads to autoimmune responses in other organ systems we harvested lung, heart, kidney and colon from naïve mice (n=3), unvaccinated tumor only mice (n=3), and vaccinated mice with CD24 Fc (n=12) or human IgG-Fc control (n=12) after tumor inoculation and vaccination therapy at day 30. The Immune cell infiltrates and immunogenic pathway signatures in different organ systems were investigated using NanoString Autoimmune Profiling arrays. Nanostring RNA transcript results were validated with immunohistochemistry staining. The whole tumor cell vaccine combined with immune checkpoint therapy triggers occult organ specific immune cell infiltrates, primarily in cardiac tissue and to a lesser extent in the renal and lung tissue, but not in the colon. CD24-Fc administration with vaccination partially impedes anti-tumor immunity but delaying CD24-Fc administration after initial vaccination reverses this effect. CD24-Fc treatment also ameliorates the autoimmune response induced by effective tumor vaccination in the heart. This study illustrates that the combination of Myc suppressed whole tumor cell vaccination with checkpoint inhibitors is an effective therapy, but occult immune infiltrates are induced in several organ systems in a mouse neuroblastoma model. The systemic administration of CD24-Fc suppresses autoimmune tissue responses, but appropriate timing of administration is critical for maintaining efficacy of the therapeutic vaccine.