PO.TB07.03 · 肿瘤生物学
顺铂与口腔微生物群在HNSCC侵袭性中的协同作用及其临床意义
Cisplatin-oral microbiota synergistic role in HNSCC aggressiveness and its clinical relevance
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摘要 Abstract
中文摘要
背景：以顺铂为基础的化疗仍是治疗头颈部鳞状细胞癌（HNSCC）的基石。然而，其治疗成功在晚期疾病（III-IIIb期）患者中往往受限。新兴证据表明，化疗本身可能诱导或选择出侵袭性、耐药性肿瘤表型。同时，口腔微生物群失调——尤其涉及具核梭杆菌（Fusobacterium nucleatum）和牙龈卟啉单胞菌（Porphyromonas gingivalis）——已被认为与HNSCC进展和免疫逃逸有关。然而，顺铂治疗与口腔微生物生态之间的协同相互作用仍知之甚少。在此，我们研究口腔微生物群是否通过重编程癌症干细胞（CSC）表型（尤其是代表对治疗诱导应激的适应性利他反应的肿瘤干性防御（TSD）状态）来增强顺铂诱导的侵袭性。方法：前瞻性收集15例HNSCC患者在开始以顺铂为基础的化疗之前的唾液样本。使用16S rRNA基因测序和针对F. nucleatum和P. gingivalis的靶向qPCR分析微生物组组成。在体外，将这些分离株与SAS HNSCC细胞共培养（MOI 50:1），并用顺铂（1-5 µM）处理三天。治疗后恢复监测长达14天，评估集落形成、迁移以及TSD相关干性标志物（EpCAM、ABCG2、HIF-2alpha、Myc、SOX2、OCT4、NANOG）的表达。在临床上，将治疗后唾液微生物群与患者结局和肿瘤缺氧特征相关联。结果：SAS细胞与顺铂及F. nucleatum或P. gingivalis共暴露导致出现TSD样表型，其特征为HIF-2alpha、ABCG2和Myc表达升高、克隆生存增加以及迁移能力增强。这种重编程效应可被TLR4抑制所减弱。患者唾液分析显示，微生物LPS负荷升高和F. nucleatum富集与化疗反应不佳以及治疗期间较高的CTC计数相关。结论：我们的发现揭示，口腔微生物群与顺铂协同作用，促进HNSCC中治疗诱导的适应性干性。这一涉及微生物LPS/TLR4信号和HIF-2alpha激活的机制提示，口腔微生物失调可能在化疗应激下充当肿瘤演变的共同驱动因素。靶向微生物群-化疗相互作用可能提供减少治疗后复发的新途径。参考文献：1. doi: 10.3389/fimmu.2024.1336882 2. doi: 10.3389/fimmu.2023.1198269 3. doi:10.1620/tjem.253.249. PMID: 33840648。
查看英文原文 English abstract
Background: Cisplatin-based chemotherapy remains a cornerstone for treating Head and NeckSquamous Cell Carcinoma (HNSCC). However, its therapeutic success is often limited inpatients with advanced-stage disease (Stage III-IIIb). Emerging evidence indicates thatchemotherapy itself may induce or select for aggressive, therapy-resistant tumor phenotypes.Meanwhile, dysbiosis of the oral microbiota-particularly involving Fusobacterium nucleatumand Porphyromonas gingivalis-has been implicated in HNSCC progression and immuneevasion. Yet, the synergistic interplay between cisplatin treatment and oral microbial ecologyremains poorly understood. Here, we investigate whether oral microbiota enhance cisplatin-induced aggressiveness via reprogramming of cancer stem cell (CSC) phenotypes, particularlythe Tumor Stemness Defense (TSD) state, which represents an adaptive altruistic response totherapy-induced stress.
Methods: Saliva samples were prospectively collected from 15 HNSCC patients prior toinitiation of cisplatin-based chemotherapy. The microbiome composition was analyzed using16S rRNA gene sequencing and targeted qPCR for F. nucleatum and P. gingivalis. In vitro,these isolates were co-cultured with SAS HNSCC cells (MOI 50:1) and treated with cisplatin(1-5 µM) for three days. Post-treatment recovery was monitored up to 14 days, withassessments of colony formation, migration, and expression of TSD-associated stemnessmarkers (EpCAM, ABCG2, HIF-2alpha, Myc, SOX2, OCT4, NANOG). Clinically, post-therapysalivary microbiota was correlated with patient outcomes and tumor hypoxia profiles.
Results: Co-exposure of SAS cells to cisplatin and F. nucleatum or P. gingivalis led to theemergence of a TSD-like phenotype, characterized by elevated expression of HIF-2alpha, ABCG2,and Myc, increased clonogenic survival, and enhanced migration capacity. Thisreprogramming effect was attenuated by TLR4 inhibition. Patient saliva analysis revealed thatelevated microbial LPS load and enrichment of F. nucleatum correlated with poorchemotherapy response and higher CTC count during treatment.
Conclusion : Our findings reveal that the oral microbiota synergizes with cisplatin to promotetherapy-induced adaptive stemness in HNSCC. This mechanism, involving microbialLPS/TLR4 signaling and HIF-2alpha activation, suggests that oral microbial dysbiosis may act asa co-driver of tumor evolution under chemotherapeutic stress. Targeting microbiota-chemotherapy interactions may offer a new avenue to reduce post-therapy relapse.
References: 1. doi: 10.3389/fimmu.2024.1336882 2. doi: 10.3389/fimmu.2023.1198269 3 . doi:10.1620/tjem.253.249. PMID: 33840648.
利益披露 Disclosure
P. J. Saikia, None..
L. Pathak, None..
B. Pal, None..
U. Sarmah, None..
T. Sarma, None..
C. Das, None..
D. Datta, None..
B. Das, None.