肿瘤细胞治疗研究
英文原题：Dexamethasone activates anti-tumor immunity in multiple myeloma by dismantling the GR-PPP1CB complex to restore STING/IRF3 signaling.
本研究揭示了一条对糖皮质激素敏感的抑制轴，其中 GR-PPP1CB 在 MM 中持续抑制 STING-TBK1-IRF3 信号通路。
背景：环鸟苷酸-腺苷酸合成酶/干扰素基因刺激因子（cGAS-STING）通路通过感知胞质DNA并产生I型干扰素介导抗肿瘤免疫，但在多发性骨髓瘤（MM）中常受抑制，进而促进免疫逃逸。地塞米松（DXM）是MM治疗中的关键糖皮质激素，尽管具有免疫抑制的传统印象，却常与免疫疗法联合使用。DXM及其糖皮质激素受体（GR）调节MM免疫微环境的机制尚不清楚。 方法：我们在5TMM3VT小鼠模型中采用单细胞RNA测序分析肿瘤免疫微环境。利用STING敲除小鼠进行遗传学验证，并以PP1抑制剂salubrinal开展药理学研究。采用共免疫沉淀、质谱和免疫荧光分析蛋白相互作用；利用共培养体系结合流式细胞术、定量实时PCR和ELISA评估NK细胞细胞毒性及巨噬细胞极化。 结果：我们发现，基础状态下GR持续募集磷酸酶PPP1CB，使TBK1-IRF3复合物去磷酸化并失活，从而抑制MM细胞cGAS-STING信号。作为GR的特异性配体，DXM迅速与GR结合，破坏GR-PPP1CB-TBK1-IRF3复合物，进而重新激活STING信号并诱导干扰素刺激基因表达。单细胞分析显示，DXM重塑免疫微环境，增强NK细胞细胞毒性并促进M1样巨噬细胞极化。STING缺失模型中，这些免疫刺激作用消失。药理性PP1抑制剂salubrinal可重现DXM的作用，与硼替佐米联合后延长体内生存，并增强达雷妥尤单抗介导的抗体依赖性细胞毒作用（ADCC）。 结论：本研究揭示一种对糖皮质激素敏感的抑制轴：GR-PPP1CB持续抑制MM中的STING-TBK1-IRF3信号。DXM解除这一抑制，重新激活先天抗肿瘤免疫。抑制PP1是增强抗骨髓瘤免疫、克服免疫逃逸的有前景治疗策略。
BACKGROUND: The cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS-STING) pathway mediates anti-tumor immunity by sensing cytosolic DNA and producing type I interferons, but is frequently suppressed in multiple myeloma (MM), enabling immune evasion. Dexamethasone (DXM), a cornerstone glucocorticoid in MM therapy, is paradoxically combined with immunotherapies despite its immunosuppressive reputation. The mechanisms by which DXM and its glucocorticoid receptor (GR) modulate the MM immune microenvironment remain elusive. METHODS: We analyzed the tumor immune microenvironment using single-cell RNA sequencing in 5TMM3VT murine models. STING-knockout mice were employed for genetic validation, and the PP1 inhibitor salubrinal for pharmacological studies. Protein-protein interactions were examined by co-immunoprecipitation, mass spectrometry, and immunofluorescence. NK cell cytotoxicity and macrophage polarization were assessed using co-culture systems with flow cytometry, quantitative real-time PCR, and ELISA. RESULTS: We identified that GR constitutively recruits the phosphatase PPP1CB to dephosphorylate and inactivate the TBK1-IRF3 complex, thereby suppressing cGAS-STING signaling in MM cells under basal conditions. As the specific ligand of GR, DXM rapidly binds to GR, leading to the disruption of the GR-PPP1CB-TBK1-IRF3 complex, which in turn reactivates STING signaling and induces interferon-stimulated gene expression. Single-cell analysis revealed that DXM remodeled the immune microenvironment, enhancing NK cell cytotoxicity, and promoting M1-like macrophage polarization. These immunostimulatory effects were abrogated in STING-deficient models. Pharmacological inhibition of PP1 with salubrinal recapitulated DXM's effects, synergized with bortezomib to prolong survival in vivo , and enhanced daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). CONCLUSIONS: This study uncovers a glucocorticoid-sensitive inhibitory axis wherein GR-PPP1CB constitutively suppresses STING-TBK1-IRF3 signaling in MM. DXM relieves this suppression, reactivating innate anti-tumor immunity. PP1 inhibition represents a promising therapeutic strategy to enhance anti-myeloma immunity and overcome immune evasion.
MEMBER ACCOUNT
登录成功会直接打开下一页。
