PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.
摘要：
背景：在三阴性乳腺癌（TNBC）治疗中，淋巴细胞浸润不足会显著阻碍免疫检查点抑制剂的疗效.我们以前已经证明海纳宁-1(HN-1)，从海南青蛙皮肤中鉴定出的宿主防御肽（HDP），诱导乳腺癌细胞凋亡，并通过未知的机制引导抗肿瘤免疫。
方法：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）指标，小鼠肿瘤模型验证HN-1促进小鼠抗肿瘤免疫应答,并对患者来源的乳腺癌细胞进行体外药敏试验，以验证HN-1的抑制作用。
结果：HN-1在TNBC中诱导ICD，在此期间释放了损伤相关分子模式（DAMPs），可以进一步增加抗肿瘤免疫反应。白细胞介素2（IL-2）的分泌水平，IL-12和干扰素γ在共培养上清液中增加，和树突细胞(DC)通过与HN-1预处理的TNBC细胞共培养而被激活。因此,HN-1增加了携带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,调节性T细胞和骨髓来源的抑制细胞受到抑制。此外,HN-1诱导DNA损伤,胞质溶胶中的双链DNA释放显着增强，表明HN-1可能通过激活STING途径刺激ICD。STING的敲低抑制HN-1诱导的ICD。值得注意的是，在三维培养条件下，HN-1对患者来源的乳腺癌细胞表现出抑制作用。
结论：总的来说，我们的研究表明,HN-1可作为一种潜在化合物,可增强TNBC患者的免疫治疗效果.
方法：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）指标，小鼠肿瘤模型验证HN-1促进小鼠抗肿瘤免疫应答,并对患者来源的乳腺癌细胞进行体外药敏试验，以验证HN-1的抑制作用。
结果：HN-1在TNBC中诱导ICD，在此期间释放了损伤相关分子模式（DAMPs），可以进一步增加抗肿瘤免疫反应。白细胞介素2（IL-2）的分泌水平，IL-12和干扰素γ在共培养上清液中增加，和树突细胞(DC)通过与HN-1预处理的TNBC细胞共培养而被激活。因此,HN-1增加了携带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,调节性T细胞和骨髓来源的抑制细胞受到抑制。此外,HN-1诱导DNA损伤,胞质溶胶中的双链DNA释放显着增强，表明HN-1可能通过激活STING途径刺激ICD。STING的敲低抑制HN-1诱导的ICD。值得注意的是，在三维培养条件下，HN-1对患者来源的乳腺癌细胞表现出抑制作用。
结论：总的来说，我们的研究表明,HN-1可作为一种潜在化合物,可增强TNBC患者的免疫治疗效果.
