Response to the Comment on “Genomic Alteration and Immunity-Implications in Esophageal Cancer”
Response to the Comment on “Genomic Alteration and Immunity-Implications in Esophageal Cancer”
复制标题
对“食管癌的基因组改变和免疫影响”评论的回应
DOI：
10.1097/sla.0000000000004942
复制
发表时间：
2021
影响因子：
9
通讯作者：
Baba Hideo
中科院分区：
文献类型：
--
作者：
Kosumi Keisuke;Baba Yoshifumi;Baba Hideo
回复：我们要感谢杜俊峰博士及其同事花时间撰写他们关于我们最近发表的研究的文章，该研究显示了食管癌组织中肿瘤长散布核苷酸元件-1（LINE-1）甲基化水平与肿瘤周围淋巴细胞反应之间的关系。1.他们仔细而深思熟虑地确定了我们研究的优点和局限性。在他们的文章中，杜等人对三点进行了重要评论。第一条评论提到了几种免疫相关标志物在食管癌中的预后作用。越来越多的证据表明淋巴细胞反应模式的预后作用。在一项利用2项美国前瞻性队列研究的综合数据库的大型人群研究中，所有4种淋巴细胞反应成分，包括克罗恩样反应、瘤内腺周反应、瘤周反应和肿瘤浸润淋巴细胞，都可能是结直肠癌的预后生物标志物。2同时，只有瘤周淋巴细胞反应在食管癌中可能具有预后作用，3尽管其潜在机制尚不清楚。我们先前报道了肿瘤程序性死亡配体1（PD-L1）表达和肿瘤吲哚胺2，3-双加氧酶（IDO 1）表达在食管癌患者中的预后作用。根据Du博士的建议，我们进行了多变量考克斯比例风险模型，包括瘤周淋巴细胞反应、肿瘤PD-L1表达、肿瘤IDO 1表达和美国癌症联合委员会疾病分期。重要的是，我们观察到所有3种免疫相关标志物都可以是独立的预后标志物以及疾病分期。肿瘤周围高水平病例的总生存期风险比为0.40 [95%置信区间（CI），0.21-0.73; P <0.0078]（vs瘤周-无/低水平病例），1.79（95% CI，1.09-2.83; P <0.022）PD-L1阳性病例（与PD-L1阴性病例相比），1.59 IDO 1阳性病例（vs IDO 1阴性病例）为2.95（95%CI，1.04-2.37; P <0.0001），III期病例（vs I期病例）为2.95（95%CI，1.85-4.82; P< 0.0001）。这一发现表明，每个免疫相关的标志物可能是一个独立的预后标志物，以及疾病stage.We以前报道的显着负相关的肿瘤浸润淋巴细胞与先进的疾病阶段。4我们还观察到瘤周淋巴细胞反应与疾病分期之间的类似关系。1第二个问题是关于肿瘤LINE-1甲基化水平与疾病分期分层中瘤周淋巴细胞反应的关系，因为肿瘤LINE-1甲基化水平与疾病分期呈负相关。这一评论提出了一个重要的观点，我们已经研究了肿瘤LINE-1甲基化水平与肿瘤周围淋巴细胞反应在疾病阶段分层的关系。在II期病例中，LINE-1与瘤周淋巴细胞反应之间的负相关性显著（P <$0.0019），在I期病例中观察到类似趋势（P <$0.076）。然而，在III期病例中没有相关性（P <0.63），表明肿瘤LINE-1对宿主免疫的影响可能因疾病分期而异。食管癌起源于一组异质性肿瘤，其由基因组和表观基因组改变的组合引起。肿瘤分子特征中的杂合性可能改变肿瘤LINE-1甲基化水平对肿瘤微环境中免疫状态的影响，这对治疗的临床疗效提出了重大挑战。
Reply: We would like to thank Dr. Junfeng Du and colleagues for taking the time to write their article regarding our recently published study showing the relationship between tumor long-interspersed nucleotide element-1 (LINE-1) methylation level and peritumoral lymphocytic reaction in esophageal carcinoma tissue. 1 They have carefully and thoughtfully identified both the strengths and limitations of our research. In their article, Du et al made important comments on 3 points. The first comment mentions the prognostic roles of several immune-related markers in esophageal cancer carcinomas. Accumulating evidence indicates a prognostic role of lymphocytic reaction patterns. In a large population-based study utilizing an integrative database of 2 US prospective cohort studies, all of the 4 lymphocytic reaction components, including Crohn-like reaction, intratumoral periglandular reaction, peritumoral reaction, and tumor-infiltrating lymphocytes might be prognostic biomarkers in colorectal carcinoma. 2 Meanwhile, only peritumoral lymphocytic reaction might have a prognostic role in esophageal cancer, 3 although the underlying mechanisms remain unclear. We previously reported the prognostic role of tumor programmed death-ligand 1 (PD-L1) expression and tumor indoleamine 2, 3-dioxygenase (IDO1) expression in esophageal cancer patients. As Dr. Du suggested, we performed a multivariable Cox proportional hazard model including peritumoral lymphocytic reaction, tumor PD-L1 expression, tumor IDO1 expression, and the American Joint Committee on Cancer disease stage. Importantly, we observed that all 3 immune-related markers could be independent prognostic markers as well as disease stage. Hazard ratios for overall survival were 0.40 [95% confidence interval (CI), 0.21–0.73; P ¼ 0.0078] for peritumoral-high cases (vs peritumoral-absent/low cases), 1.79 (95% CI, 1.09–2.83; P ¼ 0.022) for PD-L1-positive cases (vs PD-L1-negative cases), 1.59 (95% CI, 1.04–2.37; P ¼ 0.034) for IDO1-positive cases (vs IDO1-negative cases), and 2.95 (95% CI, 1.85–4.82; P< 0.0001) for stage III cases (vs stage I cases). This finding indicates that each immune-related marker might be an independent prognostic marker as well as disease stage.We previously reported the significant inverse association of tumor-infiltrating lymphocytes with advanced disease stage. 4 We also observed a similar relationship between peritumoral lymphocytic reaction and disease stage. 1 The second question is on the relationship between tumor LINE-1 methylation level and peritumoral lymphocytic reaction in strata of disease stage, as tumor LINE-1 methylation level has an inverse association with disease stage. This comment raises an important point, and we have investigated the association of tumor LINE-1 methylation level with peritumoral lymphocytic reaction in strata of disease stage. The inverse association between LINE-1 and peritumoral lymphocytic reaction was significant in Stage II cases (P ¼ 0.0019), and a similar trend was observed in Stage I cases (P ¼ 0.076). However, there was no association in stage III cases (P¼ 0.63), suggesting that the influence of tumor LINE-1 on host immunity might differ according to disease stage. Esophageal cancer originates in a heterogeneous group of neoplasms that arise from a combination of genomic and epigenomic alterations. Heterogeneity in the tumor’s molecular characteristics might modify the impact of tumor LINE-1 methylation level on immune status in the tumor microenvironment, which poses a significant challenge to the clinical efficacy of treatments.