PO.TB10.05 · 肿瘤生物学
腺苷驱动的衰老癌症相关成纤维细胞炎症性重编程促进胰腺导管腺癌中的免疫抑制
Adenosine-driven inflammatory reprogramming of aged cancer-associated fibroblasts promotes immune suppression in pancreatic ductal adenocarcinoma
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摘要 Abstract
中文摘要
背景：衰老对胰腺导管腺癌（PDAC）的肿瘤免疫微环境产生深远影响。在老年患者中，PDAC常表现为明显的间质促结缔组织增生、增强的免疫逃逸以及对化疗抵抗的增加。这些年龄相关改变的分子基础在很大程度上仍未明确。新出现的证据表明，衰老相关的代谢重编程可深刻重塑肿瘤微环境（TME）的细胞和免疫组成。然而，衰老PDAC中代谢扰动、间质细胞动态与免疫调控之间的机制性相互作用尚未完全阐明。
方法：使用bulk和单细胞转录组学及代谢组学分析了两个按年龄和生存分层的PDAC临床队列。通过靶向代谢组学评估核苷酸代谢。功能研究包括对衰老和年轻癌症相关成纤维细胞（CAF）进行腺苷刺激、B细胞迁移和共培养实验、细胞因子谱分析，以及采用腺苷受体阻断的原位PDAC小鼠模型。应用多重免疫组织化学（mIHC）在空间上验证衰老人PDAC组织中A2B⁺CXCL13⁺ CAF与IL-10⁺ Breg的邻近性。
结果：衰老PDAC表现出调节性B（Breg）细胞丰度增加，且与更短的总生存期相关。多组学分析鉴定出年龄相关的腺苷积累是与不良预后和Breg浸润均相关的最失调代谢物。直接暴露于腺苷未能扩增Breg，但将衰老CAF重编程为促炎状态。衰老CAF表达升高的腺苷受体A2B，并在腺苷刺激下分泌B细胞趋化因子CXCL13。腺苷-A2B-CXCL13轴促进IL-10⁺ Breg募集，从而抑制CD8⁺ T细胞的细胞毒性并加速肿瘤生长。mIHC证实衰老PDAC组织中CXCL13⁺ CAF与Breg之间存在紧密的空间关联。药理学抑制A2B信号或中和CXCL13可减少Breg浸润、恢复T细胞活性，并延长原位衰老PDAC模型的生存期。
结论：年龄相关的腺苷积累通过A2B受体依赖的炎症性重编程重塑成纤维细胞龛，诱导CXCL13介导的Breg募集和免疫抑制。靶向腺苷-A2B-CXCL13轴代表了在老年PDAC患者中恢复抗肿瘤免疫的一种有前景的策略。
查看英文原文 English abstract
Background: Aging exerts a profound influence on the tumor immune microenvironment of pancreatic ductal adenocarcinoma (PDAC). In elderly patients, PDAC is frequently characterized by pronounced stromal desmoplasia, enhanced immune evasion, and increased resistance to chemotherapy. The molecular underpinnings of these age-associated alterations remain largely undefined. Emerging evidence indicates that aging-related metabolic reprogramming can profoundly reshape the cellular and immunologic composition of the tumor microenvironment (TME). Yet, the mechanistic interplay between metabolic perturbations, stromal cell dynamics, and immune regulation in aged PDAC has not been fully elucidated.
Methods: Two PDAC clinical cohorts stratified by age and survival were analyzed using bulk and single-cell transcriptomics, and metabolomics. Nucleotide metabolism was assessed by targeted metabolomics. Functional studies included adenosine stimulation of aged and young cancer-associated fibroblasts (CAFs), B cell migration and co-culture assays, cytokine profiling, and orthotopic PDAC mouse models with adenosine receptor blockade. Multiplex immunohistochemistry (mIHC) was applied to spatially validate the proximity of A2B⁺CXCL13⁺ CAFs and IL-10⁺ Bregs in aged human PDAC tissues.
Results: Aged PDAC exhibited increased regulatory B (Breg) cell abundance, which correlated with shorter overall survival. Multi-omic analyses identified age-related adenosine accumulation as the most dysregulated metabolite linked to both poor prognosis and Breg infiltration. Direct adenosine exposure failed to expand Bregs but reprogrammed aged CAFs toward a proinflammatory state. Aged CAFs expressed elevated adenosine receptor A2B and secreted the B cell chemoattractant CXCL13 upon adenosine stimulation. The adenosine-A2B-CXCL13 axis promoted IL-10⁺ Breg recruitment, which suppressed CD8⁺ T cell cytotoxicity and accelerated tumor growth. mIHC confirmed close spatial association between CXCL13⁺ CAFs and Bregs within aged PDAC tissues. Pharmacologic inhibition of A2B signaling or CXCL13 neutralization reduced Breg infiltration, restored T cell activity, and prolonged survival in orthotopic aged PDAC models.
Conclusion: Age-associated adenosine accumulation reshapes the fibroblastic niche through A2B receptor-dependent inflammatory reprogramming, inducing CXCL13-mediated Breg recruitment and immune suppression. Targeting the adenosine-A2B-CXCL13 axis represents a promising strategy to restore anti-tumor immunity in elderly patients with PDAC.
利益披露 Disclosure
S. Zhu, None..
J. Lu, None..
Z. Tu, None..
H. Lin, None..
Y. Chen, None..
Y. Chen, None..
H. Zhang, None..
Z. Wang, None..
S. Chen, None.