Central Laboratory, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University (Liaoning Cancer Hospital & Institute), Shenyang, Liaoning, 110042, P. R. China.
School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, 116024, P. R. China.
Cell Commun Signal. 2024 Jul 5;22(1):352. doi: 10.1186/s12964-024-01731-6.
In triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism.
We used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1.
HN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions.
Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.
在三阴性乳腺癌（TNBC）治疗中，淋巴细胞浸润不足严重影响免疫检查点抑制剂的疗效。我们之前的研究表明，从海南青蛙皮肤中鉴定出的宿主防御肽（HDP）海南灵-1（HN-1）通过未知机制诱导乳腺癌细胞凋亡并增强抗肿瘤免疫。
我们使用体外实验观察 HN-1 处理的 TNBC 细胞系中的免疫原性细胞死亡（ICD）标志物，使用小鼠肿瘤模型验证 HN-1 促进小鼠抗肿瘤免疫反应，以及使用患者来源的乳腺癌细胞的体外药物敏感性试验验证 HN-1 的抑制作用。
HN-1 在 TNBC 中诱导 ICD，在此过程中释放损伤相关分子模式（DAMPs），进一步增强抗肿瘤免疫反应。共培养上清液中白细胞介素 2（IL-2）、IL-12 和干扰素 γ 的分泌水平增加，与 HN-1 预处理的 TNBC 细胞共培养可激活树突状细胞（DC）。结果，HN-1 增加了荷有 4T1 和 EMT6 肿瘤的小鼠模型中抗肿瘤免疫细胞（DC 和 T 淋巴细胞）的浸润。同时，抑制了调节性 T 细胞和髓源性抑制细胞。此外，HN-1 诱导 DNA 损伤，细胞质中双链 DNA 释放明显增强，表明 HN-1 可能通过激活 STING 通路诱导 ICD。STING 的敲低抑制了 HN-1 诱导的 ICD。值得注意的是，HN-1 在三维培养条件下对患者来源的乳腺癌细胞表现出抑制作用。
综上所述，我们的研究表明 HN-1 可用作增强 TNBC 患者免疫治疗效果的潜在化合物。
