PGE2介导的NK细胞重编程驱动肺腺癌获得性免疫治疗耐药
PGE2-mediated NK cell reprogramming drives acquired immunotherapy resistance in lung adenocarcinoma.
作者
作者单位
- Department of Oncology, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China.
- Chengdu Women and Children's Central Hospital, Chengdu, Sichuan, China.
- Department of Oncology, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China shenbo987@njmu.edu.cn.
摘要
中文
获得性耐药限制了程序性细胞死亡蛋白-1（PD-1）阻断在肺腺癌中的持久性，但驱动获得性耐药复发的肿瘤内在程序和免疫回路仍不清楚。本研究旨在识别获得性耐药的内在介质，并确定它们如何重塑抗肿瘤免疫。在免疫活性小鼠中建立了原位生物发光追踪的Lewis肺癌（LLC1）肺腺癌模型，并用抗PD-1治疗。通过体内全基因组CRISPR功能缺失筛选鉴定肿瘤内在调节因子，并使用诱导型四环素关闭敲低进行验证。通过肿瘤细胞Ptgs2敲低/缺失、16,16-二甲基PGE2给药、选择性EP2/EP4拮抗剂和塞来昔布治疗来探究前列腺素E2（PGE2）信号。通过流式细胞术、免疫荧光、RNA测序、cAMP测量、钙通量实验、小鼠和人NK细胞共培养细胞毒性实验以及NK细胞过继转移分析自然杀伤（NK）细胞功能。使用塞来昔布评估药理学PGE2阻断在体内的治疗潜力。分析公共免疫治疗数据集以评估PTGS2的临床相关性。原位LLC1模型 captures 异质性抗PD-1反应的关键特征，包括初始消退后复发。CRISPR筛选鉴定Ptgs2为获得性耐药的关键驱动因素。肿瘤来源的PGE2在耐药肿瘤中逐渐增加，其基因沉默通过恢复NK细胞浸润和功能克服耐药。机制上，PGE2通过EP2/EP4受体信号升高cAMP并诱导CREM，从而抑制NK细胞细胞毒性和细胞因子产生。该轴在人NK细胞中得到验证。环氧合酶-2抑制剂塞来昔布的药理学抑制逆转了获得性耐药，该效应被NK细胞耗竭消除。肿瘤来源的PGE2是肺腺癌PD-1阻断获得性耐药的重要贡献者。治疗性破坏EP2/EP4-cAMP-CREM轴可恢复NK细胞功能并克服获得性耐药。
English
Acquired resistance limits the durability of programmed cell death protein-1 (PD-1) blockade in lung adenocarcinoma, yet the tumor-intrinsic programs and immune circuits that drive acquired resistance relapse remain poorly defined. The purpose of this study was to identify tumor-intrinsic mediators of acquired resistance and determine how they remodel antitumor immunity. An orthotopic bioluminescence-tracked Lewis lung carcinoma (LLC1) lung adenocarcinoma model was established in immunocompetent mice treated with anti-PD-1. Tumor-intrinsic regulators were identified by an in vivo genome-wide CRISPR loss-of-function screen and validated using inducible tetracycline-off knockdown. Prostaglandin E2 (PGE2) signaling was interrogated through tumor-cell Ptgs2 knockdown/deletion, 16,16-dimethyl PGE2 administration, selective EP2/EP4 antagonists, and celecoxib treatment. Natural killer (NK)-cell function was analyzed by flow cytometry, immunofluorescence, RNA sequencing, cAMP measurement, calcium flux assays, mouse and human NK-cell co-culture cytotoxicity assays, and NK-cell adoptive transfer. Celecoxib was used to evaluate the therapeutic potential of pharmacologic PGE2 blockade in vivo. Public immunotherapy datasets were analyzed to assess the clinical relevance of PTGS2. The orthotopic LLC1 model captured key features of heterogeneous anti-PD-1 responses, including relapse after initial regression. The CRISPR screen identified Ptgs2 as a key driver of acquired resistance. Tumor-derived PGE2 progressively increased in resistant tumors, and its genetic silencing overcame resistance by restoring NK-cell infiltration and function. Mechanistically, PGE2 signaled through EP2/EP4 receptors to elevate cAMP and induce CREM, thereby suppressing NK-cell cytotoxicity and cytokine production. This axis was validated in human NK cells. Pharmacologic inhibition of cyclooxygenase-2 with celecoxib reversed acquired resistance, an effect abrogated by NK-cell depletion. Tumor-derived PGE2 is an important contributor to acquired resistance to PD-1 blockade in lung adenocarcinoma. Therapeutic disruption of the EP2/EP4-cAMP-CREM axis restores NK-cell function and overcomes acquired resistance.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 11.7
- 新锐分区
- 1区