Molecular Oncology Group, Spain.
Oncology Data Science Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Ann Oncol. 2020 Oct;31(10):1366-1375. doi: 10.1016/j.annonc.2020.06.003. Epub 2020 Jun 20.
Accumulating evidence has identified Fusobacterium as an important pathogenic gut bacterium associated with colorectal cancer. Nevertheless, only limited data exist about the role of this bacterium in locally advanced rectal cancer (LARC). In this study, we quantified Fusobacterium nucleatum in untreated and post-neoadjuvant chemoradiotherapy (nCRT) samples from LARC patients and investigated its association with therapy response and survival.
A total of 254 samples from 143 patients with rectal adenocarcinomas were analyzed for the presence and abundance of F. nucleatum using RNA in situ hybridization and digital image analysis. Assay accuracy was determined using infected cell lines and tumor samples with available quantitative PCR data. We studied the impact of F. nucleatum load on pathologic complete response and relapse-free survival. Treatment-induced changes were evaluated in paired pre- and post-nCRT samples (n = 71). Finally, tumor microenvironment changes during nCRT were assessed in paired samples (n = 45) by immune contexture analysis.
F. nucleatum tissue levels by RNA in situ hybridization strongly correlated with quantitative PCR (r = 0.804, P < 0.001). F. nucleatum abundance was higher in untreated [median, 7.4; 95% confidence interval (3.7-16.2)] compared with treated [median, 1.6; 95% confidence interval (1.3-2.4)] tumors (P <0.001) with 58% (73/126) and 26% (22/85) positive tumors, respectively (P < 0.001). Baseline F. nucleatum levels were not associated with pathologic complete response. F. nucleatum positivity after nCRT, but not baseline status, significantly increased risk of relapse [hazard ratio = 7.5, 95% confidence interval (3.0-19.0); P < 0.001]. Tumors that turned F. nucleatum-negative after nCRT had a strong increase in CD8+ T cells post-nCRT (P < 0.001), while those that persisted F. nucleatum-positive after nCRT lacked CD8+ T cells induction in post-nCRT samples compared with baseline (P = 0.69).
F. nucleatum persistence post-nCRT is associated with high relapse rates in LARC, potentially linked to suppression of immune cytotoxicity.
越来越多的证据表明梭杆菌属是一种与结直肠癌相关的重要致病性肠道细菌。然而，关于这种细菌在局部晚期直肠肿瘤（LARC）中的作用，仅有有限的数据。在这项研究中，我们定量检测了未经治疗和新辅助放化疗（nCRT）后的 LARC 患者样本中的具核梭杆菌，并研究了其与治疗反应和生存的关系。
使用 RNA 原位杂交和数字图像分析，对 143 例直肠腺癌患者的 254 个样本进行了 F. nucleatum 的存在和丰度检测。通过感染细胞系和具有可用定量 PCR 数据的肿瘤样本，确定了检测的准确性。我们研究了具核梭杆菌负荷对病理完全缓解和无复发生存的影响。评估了 nCRT 前后配对样本（n=71）中的治疗诱导变化。最后，通过免疫组织分析评估了 nCRT 过程中配对样本（n=45）中的肿瘤微环境变化。
RNA 原位杂交检测的 F. nucleatum 组织水平与定量 PCR 高度相关（r=0.804，P<0.001）。未经治疗的肿瘤中 F. nucleatum 的丰度较高[中位数，7.4；95%置信区间（3.7-16.2）]，而接受治疗的肿瘤中 F. nucleatum 的丰度较低[中位数，1.6；95%置信区间（1.3-2.4）]（P<0.001），阳性肿瘤分别为 58%（73/126）和 26%（22/85）（P<0.001）。基线 F. nucleatum 水平与病理完全缓解无关。nCRT 后的 F. nucleatum 阳性，但基线状态不是，显著增加了复发的风险[风险比=7.5，95%置信区间（3.0-19.0）；P<0.001]。nCRT 后 F. nucleatum 转为阴性的肿瘤在 nCRT 后 CD8+T 细胞大量增加（P<0.001），而 nCRT 后仍为 F. nucleatum 阳性的肿瘤与基线相比，在 nCRT 后样本中缺乏 CD8+T 细胞诱导（P=0.69）。
nCRT 后 F. nucleatum 的持续存在与 LARC 的高复发率相关，可能与免疫细胞毒性的抑制有关。
