PO.ET06.02 · 实验与分子治疗
靶向 DNA 损伤修复通路和 CCR2⁺ 髓系细胞以克服小细胞肺癌的放射免疫治疗耐药
Targeting DNA damage repair pathway and CCR2⁺ myeloid cell to overcome radioimmunotherapy resistance in small cell lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：小细胞肺癌（SCLC）是一种高度侵袭性的神经内分泌癌，其特征为进展迅速和复发率高。尽管免疫检查点抑制剂（ICI）与放疗（RT）联合改善了患者预后，但获得性耐药仍不可避免。本研究旨在阐明放射免疫治疗耐药的潜在机制并探索潜在的新策略。
方法：我们通过对荷瘤小鼠进行多个周期的 RT + ICI 直至产生耐药，建立了获得性放射免疫治疗耐药的小鼠 SCLC 模型。随后，对肿瘤标本进行纵向单细胞 RNA 测序（scRNA-seq）分析以验证结果。使用 Western Blot、ELISA 和 Transwell 实验研究 DNA 损伤修复（DDR）通路。在体内评估了在 RT+ICI 中加入 PARP 抑制剂（PARPi）的疗效。
结果：对放射免疫治疗耐药小鼠 SCLC 模型的分析显示 DDR 活性增强、CCL2 分泌升高以及 CCR2⁺ 髓系来源抑制细胞（MDSC）浸润增加，这些结果进一步经纵向 scRNA-seq 验证。靶向 CCL2-CCR2 轴显著延迟了 RT + ICI 治疗后的肿瘤复发。接下来，在体外，PARPi 与 RT 联合协同抑制了 DDR 激活并抑制了 CCL2 依赖性 MDSC 迁移。在体内，与 RT + ICI 治疗相比，PARPi 与 RT + ICI 同时给药对于实现更好的肿瘤控制和生存获益至关重要，而延迟给予 PARPi 则无效。肿瘤微环境分析表明三联疗法（RT + ICI + 同期 PARPi）有效抑制了 DDR 通路，显著减少了 CCR2⁺ MDSC 浸润，并增加了效应 T 细胞募集。
结论：DDR 驱动的 CCL2 分泌募集 CCR2⁺ MDSC 以介导 SCLC 的放射免疫治疗耐药。PARPi 通过双重阻断肿瘤 DDR 和 MDSC 募集来破坏这一轴。我们的数据揭示了将同期 PARPi 与放化免疫治疗联合作为 ES-SCLC 一线治疗值得探索，一项前瞻性临床试验正在进行中（NCT06217757）。
查看英文原文 English abstract
Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine carcinoma characterized by rapid progression and a high relapse rate. Although the combination of immune checkpoint inhibitors (ICIs) with radiotherapy (RT) has improved patient outcomes, acquired resistance remains inevitable. This study aims to elucidate the underlying mechanisms of radioimmunotherapy resistance and explore potential novel strategies.
Methods: We established a murine SCLC model of acquired radioimmunotherapy resistance by subjecting tumor-bearing mice to multiple cycles of RT + ICI until resistance developed. Subsequently, longitudinal single-cell RNA sequencing (scRNA-seq) analysis of tumor specimens was performed to validate the findings. The DNA damage repair (DDR) pathway was investigated using Western Blot, ELISA, and Transwell assays. The efficacy of adding PARP inhibitor (PARPi) to RT+ICI was evaluated in vivo .
Results: Analysis of the radioimmunotherapy-resistant murine SCLC model revealed that enhanced DDR activity, elevated CCL2 secretion, and increased of infiltration of CCR2⁺ myeloid-derived suppressor cells (MDSCs), which were further validated by longitudinal scRNA-seq. Targeting the CCL2-CCR2 axis significantly delayed tumor relapse following RT + ICI treatment. Next, i n vitro , combining PARPi with RT synergistically suppressed DDR activation and inhibited CCL2-dependent MDSC migration. In vivo , concurrent administration of PARPi with RT + ICI was essential for achieving better tumor control and survival benefit compared with RT + ICI treatment, whereas delayed intervention of PARPi proved ineffective. Tumor microenvironment analysis demonstrated that the triple therapy (RT + ICI + concurrent PARPi) effectively suppressed the DDR pathway, significantly reduced CCR2⁺ MDSC infiltration, and increased effector T cell recruitment.
Conclusion: DDR-driven CCL2 secretion recruits CCR2⁺ MDSCs to mediate radioimmunotherapy resistance in SCLC. PARPi disrupts this axis through dual blockade of tumor DDR and MDSC recruitment. Our data revealed that the combination of concurrent PARPi with radio-chemo-immunotherapy as first line therapy in ES-SCLC is worth exploring and a prospective clinical trial is ongoing (NCT06217757).
利益披露 Disclosure
Z. Yao, None..
K. Kang, None.