Abstract：
Programmed death ligand 1, PD-L1 (CD274), facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic hedgehog (Shh) and transforming growth factor β receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBCs), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein, caprin-1, to stabilize Shh/TGFBR1/Wnt mRNAs to induce β-catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ regulatory T cells and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.
摘要：
程序性死亡配体1，PD-L1（CD274），促进免疫逃避并在癌细胞中发挥促生存功能。这里,我们报道了一种机制，即PD-L1内化响应于神经酰胺合酶4（CerS4）引起的生物活性脂质/神经酰胺代谢的改变，从而诱导声波刺猬（Shh）和转化生长因子β受体信号传导以增强三阴性乳腺癌的肿瘤转移（TNBC），表现出免疫疗法抗性。机械上,数据显示内化的PD-L1与RNA结合蛋白相互作用，caprin-1，稳定Shh/TGFBR1/WntmRNA，诱导β-catenin信号和TNBC生长/转移，与FoxP3+调节性T细胞浸润增加和对免疫疗法的抗性一致。虽然在MMTV-PyMT/CerS4-/-中发展的乳腺肿瘤是高度转移性的，使用Sonidegib和抗PD-L1抗体靶向Shh/PD-L1轴大大降低了肿瘤的生长和转移，与PD-L1内化和Shh/Wnt信号的抑制一致，恢复抗肿瘤免疫反应。这些数据,在临床样本和数据库中验证，提供了一种基于机制的治疗策略，以改善转移性TNBC的免疫治疗反应。
