■无反应性是当前癌症免疫检查点阻断疗法的主要障碍,机制尚未阐明。因此,有必要发现肿瘤免疫治疗耐药的机制和生物标志物。
■基于多个肿瘤数据库中的CD8+T细胞浸润进行生物信息学分析,以筛选出与抗肿瘤免疫相关的基因。G蛋白信号调节因子1(RGS1)和IFNγ-STAT1信号之间的关联,通过RT-qPCR检查MHCI抗原呈递途径,西方印迹,和流式细胞术。通过CHIP-qPCR和双荧光素酶测定研究了RGS1的调节机制。使用肿瘤细胞系全面研究了RGS1的临床和治疗意义,小鼠模型,和接受免疫治疗的临床样本。
■RGS1被鉴定为RGS家族中与免疫原性正相关的最高基因。肿瘤细胞中RGS1的抑制减弱了抗肿瘤免疫反应,并在肾和肺小鼠皮下肿瘤中引起对免疫疗法的抵抗。机械上,RGS1增强了激活转录因子3(ATF3)与干扰素γ受体1(IFNGR1)启动子的结合,激活的STAT1和随后的IFNγ诱导基因的表达,特别是CXCL9和MHCI类(MHCI),从而影响CD8+T细胞浸润和抗原呈递和加工。临床上,在接受免疫治疗的21例NSCLC患者中,RGS1表达水平降低与PD1抑制治疗耐药和无进展生存期缩短相关.
■一起,这些发现揭示了引发免疫治疗耐药的新机制,并突出了肿瘤固有RGS1的功能,这为未来致敏抗PD1免疫治疗的策略带来了新的见解.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.