Tumor-intrinsic RGS1 potentiates checkpoint blockade response via ATF3-IFNGR1 axis.
Tumor-intrinsic RGS1 potentiates checkpoint blockade response via ATF3-IFNGR1 axis.
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DOI：
10.1080/2162402x.2023.2279800
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发表时间：
2023
期刊：
影响因子：
7.2
通讯作者：
中科院分区：
文献类型：
--
作者：
无反应性是目前癌症免疫检查点阻断治疗的主要障碍，其机制尚未阐明。因此，有必要探索肿瘤免疫耐药的机制和生物标志物。基于多个肿瘤数据库中的CD 8 + T细胞浸润进行生物信息学分析，筛选出与抗肿瘤免疫相关的基因。通过RT-qPCR、Western blotting和流式细胞术检测G蛋白信号调节因子1（Regulator of G-protein signaling 1，RGS 1）和IFNγ-STAT 1信号通路与MHCI抗原提呈通路之间的关系。通过CHIP-qPCR和双荧光素酶试验研究RGS 1的调节机制。使用肿瘤细胞系、小鼠模型和接受免疫治疗的临床样本全面研究了RGS 1的临床和治疗意义。RGS 1是RGS家族中与免疫原性相关性最高的基因。抑制肿瘤细胞中的RGS 1抑制抗肿瘤免疫应答，并在肾和肺小鼠皮下肿瘤中引起对免疫治疗的抗性。在机制上，RGS 1增强了转录激活因子3（ATF 3）与干扰素γ受体1（IFNGR 1）启动子的结合，激活了STAT 1，并随后表达了IFNγ诱导基因，特别是CXCL 9和MHC I类（MHCI），从而影响了CD 8 + T细胞浸润以及抗原呈递和加工。在临床上，RGS 1的低表达水平与PD 1抑制治疗的耐药和21例接受免疫治疗的NSCLC患者的无进展生存期缩短相关。总之，这些发现揭示了一种新的机制，增强了免疫疗法的耐药性，并突出了肿瘤内在RGS 1的功能，这为未来抗PD 1免疫疗法的敏化策略带来了新的见解。
Non-responsiveness is a major barrier in current cancer immune checkpoint blockade therapies, and the mechanism has not been elucidated yet. Therefore, it is necessary to discover the mechanism and biomarkers of tumor immunotherapeutic resistance. Bioinformatics analysis was performed based on CD8+ T cell infiltration in multiple tumor databases to screen out genes related to anti-tumor immunity. Associations between Regulator of G-protein signaling 1 (RGS1) and IFNγ-STAT1 signaling, and MHCI antigen presentation pathway were examined by RT-qPCR, western blotting, and flow cytometry. The modulatory mechanisms of RGS1 were investigated via CHIP-qPCR and dual-luciferase assay. The clinical and therapeutic implications of RGS1 were comprehensively investigated using tumor cell lines, mouse models, and clinical samples receiving immunotherapy. RGS1 was identified as the highest gene positively correlated with immunogenicity among RGS family. Inhibition of RGS1 in neoplastic cells dampened anti-tumor immune response and elicited resistance to immunotherapy in both renal and lung murine subcutaneous tumors. Mechanistically, RGS1 enhanced the binding of activating transcription factor 3 (ATF3) to the promoter of interferon gamma receptor 1 (IFNGR1), activated STAT1 and the subsequent expression of IFNγ-inducible genes, especially CXCL9 and MHC class I (MHCI), thereby influenced CD8+ T cell infiltration and antigen presentation and processing. Clinically, lower expression level of RGS1 was associated with resistance of PD1 inhibition therapy and shortened progression-free survival among 21 NSCLC patients receiving immunotherapy. Together, these findings uncover a novel mechanism that elicits immunotherapy resistance and highlight the function of tumor-intrinsic RGS1, which brings new insights for future strategies to sensitize anti-PD1 immunotherapy.
影响因子：
3.7
作者：
Dai J;Gu J;Lu C;Lin J;Stewart D;Chang D;Roth JA;Wu X
通讯作者：
Wu X