PO.TB03.01 · 肿瘤生物学
通过西达本胺及化疗免疫疗法选择性清除衰老的癌症相关成纤维细胞治疗转移性胰腺癌：2期临床试验结果（PANDA-1706）
Selectively eliminating senescent cancer-associated fibroblasts via chidamide and chemo-immunotherapy in metastatic pancreatic cancer: phase 2 clinical trial results (PANDA-1706)
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摘要 Abstract
中文摘要
早期胰腺导管腺癌（PDAC）中的淋巴结转移（LNM）预示着全身播散和不良生存，但其潜在机制仍不明确。在此，我们证明衰老的癌症相关成纤维细胞（senCAFs）驱动早期PDAC中的淋巴管重塑和LNM，并预示远处转移。通过基因或药理学方法清除senCAFs可抑制LNM和远处转移。机制上，senCAFs通过增强葡萄糖代谢和乳酸生成促进淋巴管生成和LNM，后者激活乳酸化介导的丝氨酸代谢以保护淋巴内皮细胞免受氧化应激。此外，利用先进的多重成像技术，我们发现来自引流淋巴结的CCR4+ Tregs聚集在淋巴管周围。这种局部聚集由富含senCAFs的淋巴内皮所促进，从而建立了一个免疫抑制性的淋巴周围微环境。此外，高通量药物筛选平台确定，通过西达本胺（一种HDAC抑制剂）选择性清除senCAFs，在低浓度下可减弱肿瘤进展并提高化疗免疫治疗的疗效。随后，我们在转移性PDAC患者中启动了一项2期临床试验。在此，我们报告西达本胺组（西达本胺和白蛋白结合型紫杉醇/吉西他滨加抗PD-1/CTLA-4）的结果。该组预先设定的主要终点已达成，获得了经确认的客观缓解率。总之，这些发现揭示了细胞衰老、代谢重编程、空间免疫抑制微环境与PDAC转移之间的紧密联系，提供了潜在的抗衰老（senolytic）手段来提高PDAC患者化疗免疫治疗的疗效。ClinicalTrials.gov标识符：NCT06951997。
查看英文原文 English abstract
Lymph node metastasis (LNM) in early-stage pancreatic ductal adenocarcinoma (PDAC) predicts systemic dissemination and poor survival, yet its underlying mechanisms remain elusive. Here, we demonstrate that senescent cancer-associated fibroblasts (senCAFs) drive lymphatic remodeling and LNM in early-stage PDAC and predict distant metastasis. Genetic or pharmacologic elimination of senCAFs suppresses LNM and distant metastasis. Mechanistically, senCAFs promote lymphangiogenesis and LNM by augmenting glucose metabolism and lactate production, which activates lactylation-mediated serine metabolism to protect lymphatic endothelial cells from oxidative stress. Moreover, using advanced multiplex imaging techniques, we have discovered that CCR4 + Tregs from the draining lymph nodes accumulated around lymphatic vessels. This localized accumulation is facilitated by lymphatic endothelia enriched in senCAFs, which established an immunosuppressive peri-lymphatic niche. Furthermore, high throughput drug screening platform determines selective clearance of senCAFs via chidamide, one HDAC inhibitor, attenuates tumor progression and improves chemo-immunotherapeutic efficacy at low concentrations. We subsequently initiated a phase 2 clinical trial in metastatic PDAC patients. Here we report the results of the chidamide arm (chidamide and nab-paclitaxel/gemcitabine plus anti-PD-1/CTLA-4). The pre-specified primary endpoint of this arm was met, with a confirmed objective response rate. Collectively, these findings reveal a closed link between cellular senescence, metabolic reprograming, spatial immusuppressive niche and PDAC metastasis, offering the potential senolytic means to improve chemo-immunotherapy efficacy in PDAC patients. Clinical Trials.gov. identifier: NCT06951997.
利益披露 Disclosure
T. Zhou, None.