一种用于克服非小细胞肺癌治疗中抗原异质性的多靶向 CAR-T 细胞平台
A Multi-Targeting Chimeric Antigen Receptor-T Cell Platform to Overcome Antigen Heterogeneity in the Treatment of Non-Small Cell Lung Cancer.
这些发现支持采用多靶点CAR-T 策略来应对NSCLC及可能其他实体瘤中的抗原异质性。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
转录因子 FOXA1 上调 PYCR1 介导的自噬以抑制肺腺癌的抗肿瘤免疫
英文原题：The transcription factor FOXA1 upregulates PYCR1-mediated autophagy to suppress antitumor immunity in lung adenocarcinoma.
查看英文原题
The transcription factor FOXA1 upregulates PYCR1-mediated autophagy to suppress antitumor immunity in lung adenocarcinoma.
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研究概要
FOXA1 上调 PYCR1 表达，激活 LUAD 细胞自噬，并削弱 CD8+ T 细胞抗肿瘤免疫应答。靶向 FOXA1/PYCR1 可能是改善 LUAD 免疫治疗的潜在途径。
研究思路结论见上方概要
背景
近年来，免疫治疗已成为肺腺癌（LUAD）的一种有效治疗方法。然而，癌细胞通过多种机制抑制抗肿瘤免疫反应的能力已成为治疗的主要挑战之一。PYCR1能够增强LUAD细胞的增殖，但PYCR1在LUAD中对抗肿瘤免疫反应的功能尚未完全阐明。
方法
通过生物信息学分析探讨PYCR1在LUAD中的临床意义以及PYCR1表达与CD8 + T细胞浸润的关系。通过免疫组化分析LUAD临床样本中PYCR1和CD8的表达。通过qPCR检测LUAD细胞模型中PYCR1的表达。采用流式细胞术、乳酸脱氢酶试剂盒、Calcein-AM/PI染色和Transwell分析PYCR1对CD8 + T细胞功能的影响。利用Western blot和免疫荧光探讨PYCR1对自噬的影响。通过双荧光素酶实验和ChIP实验评估PYCR1与FOXA1之间的相互作用。最后，进行体外和体内回补实验以验证FOXA1/PSYR1轴在LUAD免疫调节中的作用。
结果
PYCR1在LUAD中表达上调，并与患者的不良预后相关。在LUAD中敲低PYCR1显著增强了外周CD8+ T细胞的活性，并促进了LUAD细胞的死亡。此外，PYCR1的过表达激活了癌细胞中的自噬，并削弱了CD8+ T细胞的抗肿瘤免疫应答。FOXA1是PYCR1的上游转录激活因子。敲低FOXA1通过抑制自噬增强了CD8+ T细胞对LUAD细胞的杀伤能力，而PYCR1的过表达逆转了FOXA1敲低的效果，这在小鼠实验中得到了验证。
展开英文摘要原文
BACKGROUND
Immunotherapy has emerged as an effective treatment for lung adenocarcinoma (LUAD) in recent years. However, the ability of cancer cells to suppress antitumor immune responses through multiple mechanisms has become one of the major challenges for therapy. PYCR1 can reinforce the proliferation of LUAD cells, but the function of PYCR1 in LUAD against the tumor immune response has not been fully elucidated.
METHODS
The clinical significance of PYCR1 in LUAD and the relationship between PYCR1 expression and CD8 + T cell infiltration were examined by bioinformatics analysis. The expression of PYCR1 and CD8 in LUAD clinical samples was analyzed by immunohistochemistry. The expression of PYCR1 in the LUAD cell model was detected by qPCR. Flow cytometry, lactate dehydrogenase kit, Calcein-AM/PI staining, and Transwell were employed to analyze the effect of PYCR1 on CD8 + T cell function. Western blot and immunofluorescence were utilized to probe into the effect of PYCR1 on autophagy. The interaction between PYCR1 and FOXA1 was evaluated by dual-luciferase assay and ChIP assay. Finally, in vitro and in vivo rescue experiments were conducted to verify the role of the FOXA1/PSYR1 axis in the immune regulation of LUAD.
RESULTS
PYCR1 was upregulated in LUAD and was linked with the dismal prognosis of patients. Knockdown of PYCR1 in LUAD remarkably enhanced the activity of peripheral CD8 + T cells and facilitated the death of LUAD cells. In addition, overexpression of PYCR1 activated autophagy in cancer cells and dampened the anti-tumor immune response of CD8 + T cells. FOXA1 was an upstream transcriptional activator of PYCR1. Knockdown of FOXA1 potentiated the killing ability of CD8 + T cells on LUAD cells by repressing autophagy, while overexpression of PYCR1 reversed the effect of FOXA1 knockdown, which was verified in mouse experiments.
CONCLUSION
FOXA1 upregulates PYCR1 expression, activates autophagy in LUAD cells, and dampens CD8 + T cell antitumor immune response. Targeting FOXA1/PYCR1 may be a potential approach to improve LUAD immunotherapy.
论文信息
- 作者
- Liu K、Yang X、Tang X、Tang B
- 第一作者单位
- Department of Thoracic and Cardiovascular Surgery, Zigong Fourth People's Hospital, No. 19 Tanmulin Street, Ziliujing District, Zigong City, 643000, China.China
- 通讯作者单位
- Department of Thoracic and Cardiovascular Surgery, Zigong Fourth People's Hospital, No. 19 Tanmulin Street, Ziliujing District, Zigong City, 643000, China. tangb2022@163.com.China
- 期刊
- Cancer immunology, immunotherapy : CII2025 Aug 23
- 原文标识
- PubMed 40848149 · DOI 10.1007/s00262-025-04144-7
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