PO.TB10.17 · 肿瘤生物学
靶向 Spns2 诱导免疫原性细胞死亡和全身抗肿瘤免疫以抑制转移
Targeting Spns2 induces immunogenic cell death and systemic anti-tumor immunity to suppress metastasis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：Spinster 同源物 2（SPNS2）输出鞘氨醇-1-磷酸（S1P）以促进致癌信号传导。尽管 SPNS2 与转移进展相关，但其在调节免疫原性细胞死亡（ICD）和抗肿瘤免疫方面的肿瘤内在作用仍不清楚。我们研究了 SPNS2 的遗传或药理学抑制如何影响转移、ICD 诱导和全身免疫激活。
方法：结合乳腺癌（4T1、EMT6）和黑色素瘤（B16）模型分析患者数据集。使用 CRISPR 敲除 SPNS2 或使用首创（first-in-class）小分子 SPNS2 抑制剂进行抑制。在体外评估 S1P 输出、迁移及 S1PR1-AKT 信号传导。采用原位、尾静脉、共注射和疫苗接种模型评估肿瘤生长、转移扩散、ICD 特征及全身免疫。破坏单个 DAMP 通路以检验机制需求。
结果：高 SPNS2 表达在多种癌症类型中与不良生存相关。SPNS2 促进 S1P 输出、S1PR1-AKT 激活、上皮-间质转化、干性及肺定植，而 SPNS2 缺失损害迁移并显著减少自发性和实验性转移。SPNS2 抑制引发了 ICD 的标志性特征——包括 eIF2alpha 磷酸化、钙网蛋白暴露及 ATP/HMGB1 释放——增强抗原呈递，扩增 CD4⁺ 和 CD8⁺ T 细胞，并限制原发肿瘤生长、转移及术后复发。以 SPNS2 缺陷或抑制剂处理的肿瘤细胞进行疫苗接种，可保护机体抵抗 4T1 或抗原性不同的 EMT6 肿瘤的再攻击。破坏单个 DAMP 通路减弱了这些应答，证明了对 ICD 的依赖性。结论：SPNS2 介导的 S1P 转运驱动转移和免疫逃逸，而 SPNS2 抑制诱导 ICD 和强效的全身 T 细胞免疫。靶向 SPNS2 代表了一种抑制转移进展并产生持久抗肿瘤免疫的治疗策略。
披露：使用了生成式 AI 协助编辑本摘要。
查看英文原文 English abstract
Background: Spinster homolog 2 (SPNS2) exports sphingosine-1-phosphate (S1P) to promote oncogenic signaling. Although SPNS2 is associated with metastatic progression, its tumor-intrinsic role in regulating immunogenic cell death (ICD) and anti-tumor immunity remains unclear. We examined how genetic or pharmacologic inhibition of SPNS2 influences metastasis, ICD induction, and systemic immune activation.
Methods: Patient datasets were analyzed in conjunction with breast (4T1, EMT6) and melanoma (B16) models. SPNS2 was ablated using CRISPR or inhibited using a first-in-class small-molecule SPNS2 inhibitor. S1P export, migration, and S1PR1-AKT signaling were assessed in vitro. Orthotopic, tail-vein, co-injection, and vaccination models were used to evaluate tumor growth, metastatic spread, ICD signatures, and systemic immunity. Individual DAMP pathways were disrupted to test mechanistic requirements.
Results: High SPNS2 expression correlated with poor survival across multiple cancer types. SPNS2 promoted S1P export, S1PR1-AKT activation, epithelial-mesenchymal transition, stemness, and lung colonization, whereas SPNS2 loss impaired migration and markedly reduced spontaneous and experimental metastases. SPNS2 inhibition elicited hallmark ICD features-including eIF2alpha phosphorylation, calreticulin exposure, and ATP/HMGB1 release-enhancing antigen presentation, expanding CD4⁺ and CD8⁺ T cells, and limiting primary tumor growth, metastasis, and postsurgical relapse. Vaccination with SPNS2-deficient or inhibitor-treated tumor cells protected against rechallenge with 4T1 or antigenically distinct EMT6 tumors. Disruption of individual DAMP pathways attenuated these responses, demonstrating ICD dependence. Conclusions: SPNS2-mediated S1P transport drives metastasis and immune evasion, whereas SPNS2 inhibition induces ICD and potent systemic T-cell immunity. Targeting SPNS2 represents a therapeutic strategy to suppress metastatic progression and generate durable anti-tumor immunity.
Disclosure: Generative AI was used to assist in editing this abstract.
利益披露 Disclosure
H. Lee, None..
W. Wofford, None..
A. H. Janneh, None..
P. Chakarborty, None..
N. Oleinik, None..
O. Darawshi, None..
N. Parikh, None..
S. Berto, None.
K. R. Lynch,
S1P Therapeutics Inc co-founder.
W. L. Santos,
S1P Therapeutics Inc co-founder.
Ö. Şahin,
OncoCube Therapeutics LLC co-founder and manager.
LoxiGen founder and president.
A2A Pharmaceuticals Inc g., Board of Directors, non-salaried role).
S. Mehrotra,
Lipo-Immuno Tech, LLC g., Board of Directors, non-salaried role).
B. Ogretmen,
Lipo-Immuno Tech, LLC g., Board of Directors, non-salaried role).