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. 2021 Apr 20;24(4):254-264.
doi: 10.3779/j.issn.1009-3419.2021.103.05.

[CD45RO⁺ Memory T Lymphocytes As A Candidate Marker for Non-small Cell Lung Cancer]

[Article in Chinese]
Qifan Tan  1 , Haoyang Li  1 , Mengjun Yu  1 , Xiaonan Tang  1 , Jinjing Tan  2 , Shucai Zhang  1 , Jinghui Wang  1   2
Affiliations

[CD45RO⁺ Memory T Lymphocytes As A Candidate Marker for Non-small Cell Lung Cancer]

[Article in Chinese]
Qifan Tan et al. Zhongguo Fei Ai Za Zhi. .

Abstract
in English, Chinese

Background: Lung cancer is the most common malignancy world-wide. There are a variety of immune infiltrating cells in tumor microenvironment, which is an important component of tumor immunity and has clinical significance for the prognosis of patients. CD45RO is a surface marker of memory T cells. The expression of CD45RO⁺ tumor infiltrating lymphocytes (TILs) is associated with the prognosis of many tumors. The purpose of this study was to evaluate the relationship between the density of CD45RO⁺ TILs in tumor and stromal area and the clinical characteristics of patients with non-small cell lung cancer (NSCLC) and its impact on the prognosis of patients. We aimed to explore the clinical value of CD45RO⁺ TILs and programmed cell death ligand 1 (PD-L1) as prognostic markers.

Methods: Multiple fluorescent immunohistochemical staining was used to stain the tissue microarray chips of 167 patients with NSCLC, marking CD45RO, cytokeratin (CK) and PD-L1. Using artificial intelligence image recognition technology and tumor cell-specific CK staining, divide the tumor and stromal area in the tissue, evaluate the density of CD45RO⁺ TILs in the tumor and stromal area, and the expression level of PD-L1 in tumor cells. The non-parametric test was used to analyze the relationship between CD45RO⁺ TILs and the clinical characteristics of patients, and the Kaplan-Meier method and Cox risk ratio model were used to analyze the relationship between CD45RO⁺ TILs independently or in combination with PD-L1 and tumor prognosis.

Results: The density of CD45RO⁺ TILs was significantly associated with patient age, smoking, tumor stage, and pathological type. Single-factor survival analysis showed that NSCLC (P=0.007) stromal region and lung adenocarcinoma (LUAD) (P<0.001) with CD45RO⁺ TILs high density had better OS. Multivariate survival analysis showed that the high density of CD45RO⁺ TILs in the stromal region of NSCLC (HR=0.559, 95%CI: 0.377-0.829, P=0.004) and lung adenocarcinoma (HR=0.352, 95%CI: 0.193-0.641, P=0.001) were independent prognostic factors for overall survival time (OS). Combined with PD-L1 score of tumor cells in tumor tissues and infiltration score of CD45RO⁺ TILs in all tumor tissues, the patients were divided into 4 groups: patients with PD-L1⁺/CD45RO⁺ had the longest disease-free survival (DFS) time, and patients with PD-L1⁺/CD45RO- had the shortest DFS time. Multivariate Cox regression analysis showed that PD-L1⁺/CD45RO- was an independent prognostic factor for DFS and had a higher risk of poor prognosis compared to the other three groups (HR=2.221, 95%CI: 1.258-3.919, P=0.006).

Conclusions: In tumor tissues, the density of CD45RO⁺ TILs, as well as the combination of CD45RO⁺ TILs and PD-L1 in tumor areas, significantly correlated with clinicopathological features and prognosis of NSCLC, which can be used as a new prognosis marker.

【中文题目：CD45RO⁺记忆T细胞作为非小细胞肺癌患者 预后标志物的研究】 【中文摘要：背景与目的 肺癌是世界范围内最常见的恶性肿瘤之一。肿瘤微环境中多种多样的免疫浸润细胞，是肿瘤免疫的重要组成，对患者预后具有临床意义。CD45RO⁺肿瘤浸润淋巴细胞（tumor infiltrating lymphocytes, TILs），即记忆T细胞，其表达与多种肿瘤预后相关。本研究旨在探讨非小细胞肺癌（non-small cell lung cancer, NSCLC）中评估肿瘤和基质区CD45RO⁺ TILs密度与患者临床特征和预后的关系，及其联合程序性死亡受体配体1（programmed cell death-ligand 1, PD-L1）作为预后标志物的临床价值。方法 对167例NSCLC患者的组织微阵列进行多重荧光免疫组织化学染色，标记CD45RO、细胞角蛋白（cytokeratin, CK）和PD-L1。利用人工智能图像识别技术和肿瘤细胞特异性CK染色，划分组织中的肿瘤区和基质区，评估肿瘤区和基质区CD45RO⁺ TILs的密度以及肿瘤细胞的PD-L1表达水平。采用非参检验分析CD45RO⁺ TILs与患者临床特征的关系，使用Kaplan-Meier方法和Cox风险比例模型分析CD45RO⁺ TILs独立或与PD-L1联合与肿瘤预后的关系。结果 CD45RO⁺ TILs的密度与患者年龄、吸烟、肿瘤分期和病理类型显著相关。在NSCLC和肺腺癌（lung adenocarcinoma, LUAD）患者中，基质区高密度CD45RO⁺ TILs具有更长的总生存期（overall survival, OS）（NSCLC: P=0.007; LUAD: P<0.001），并且是OS的独立预后因素（NSCLC: HR=0.559, 95%CI: 0.377-0.829, P=0.004; LUAD: HR=0.352, 95%CI: 0.193-0.641, P=0.001）。联合肿瘤细胞的PD-L1评分以及所有区域CD45RO⁺ TILs的浸润评分将患者分为四组：其中PD-L1⁺/CD45RO⁺患者无病生存期（disease-free survival, DFS）最长，PD-L1⁺/CD45RO-的患者DFS时间最短，并可作为DFS预后的独立因素（HR=2.221, 95%CI: 1.258-3.919, P=0.006）。结论 肿瘤组织中CD45RO⁺ TILs密度以及CD45RO⁺ TILs联合肿瘤区PD-L1，与NSCLC的临床病理特征及预后显著相关，可作为新的生存预后标志物。】 【中文关键词：肺肿瘤；CD45RO；程序性死亡受体-配体1；预后】.

Keywords: CD45RO; Lung neoplasms; Prognosis; Programmed cell death ligand 1.

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Conflict of interest statement

【Competing interests】 The authors declare that they have no competing interests.

Figures

图 1
图 1
多标记免疫荧光染色后CD45RO和PD-L1在非小细胞肺癌中的表达。A：CD45RO、PD-L1、CK表达及DAPI染色的共定位图片（×200）；B：CK表达（细胞质，绿色）（×200）；C：PD-L1表达（细胞膜，黄色）（×200）；D：CD45RO+表达（细胞膜，红色）（×200）；E：CD45RO-表达（T淋巴细胞膜，红色）（×200）；F：肿瘤区和基质区依照组织细胞形态和CK表达情况进行划分：肿瘤区（绿色），基质区（红色）（×200） CD45RO and PD-L1 expression in non-small cell lung cancer by multiplex immunofluorescence staining. A: a merged picture of expression of CD45RO, PD-L1, CK and DAPI (×200); B: CK expression (cytoplasmic, Green) (×200); C: PD-L1 expression (Cell membrane, Yellow) (×200); D: CD45RO+ expression (Cell membrane, Red) (×200); E: CD45RO- expression (Cell membrane, Red) (×200); F: tumor compartments and stromal compartments divided by CK, Tumor (Green), stromal (Red) (×200)
图 2
图 2
非小细胞肺癌中CD45RO+ TILs与临床病理特征的关系。A：根据年龄；B：根据吸烟；C：根据临床分期；D：根据病理类型。 Significance of CD45RO+ TILs with clinicopathologic characteristics in non-small cell lung cancer. A: according to age; B: according to smoking; C: according to clinical stage; D: according to pathological type. TILs: tumor infiltrating lymphocytes; ADC: lung adenocarcinoma; SCC: lung squamous cell carcinoma
图 3
图 3
肺腺癌及肺鳞癌中CD45RO+ TILs与临床病理特征的关系。A：肺腺癌中CD45RO+ TILs密度与吸烟的关系；B：肺鳞癌CD45RO+ TILs密度与临床分期的关系 Relationship between CD45RO+ TILs and clinicopathological features in lung adenocarcinoma and lung squamous cell carcinoma. A: relationship between CD45RO+ TILs density and smoking in lung adenocarcinoma; B: relationship between CD45RO+ TILs density and clinical stage in lung squamous cell carcinoma.
图 4
图 4
CD45RO+ TILs与无病生存期以及总生存期的Kaplan-Meier曲线分析。A：非小细胞肺癌基质区CD45RO+ TILs密度与患者总生存期显著相关；B：肺腺癌基质区CD45RO+ TILs密度与患者无病生存期密切相关；C：肺腺癌基质区CD45RO+ TILs密度与患者总生存期密切相关。 Kaplan-Meier curves for Correlations of CD45RO+ TILs with disease-free survival and overall survival. A: the density of CD45RO+ TILs in the stromal compartment of non-small cell lung cancer was significantly associated with patient overall survival; B: the density of CD45RO+ TILs in the stromal compartment of lung adenocarcinoma was strongly associated with patient disease-free survival; C: the density of CD45RO+ TILs in the stromal region of lung adenocarcinoma was strongly associated with patients' OS; OS: overall survival; DFS: disease-free survival.
图 5
图 5
CD45RO+ TILs联合PD-L1的表达与无病生存期以及总生存期的Kaplan-Meier分析。A：PD-L1+/CD45RO+组非小细胞肺癌患者无病生存期最长，PD-L1+/CD45RO-组最短；B：PD-L1+/CD45RO+组非小细胞肺癌患者总生存期最长，PD-L1+/CD45RO-组最短；C：在肺腺癌中，PD-L1-/CD45RO+组较其他三组有更好的总生存期 Kaplan-Meier curves for correlations of CD45RO+ TILs and PD-L1 expression with disease-free survival and overall survival. A: patients with non-small cell lung cancer in the PD-L1+/CD45RO+ group had the longest disease-free survival and those in the PD-L1+/CD45RO- group had the shortest; B: non-small cell lung cancer patients in the PD-L1+/CD45RO+ group had the longest overall survival and those in the PD-L1+/CD45RO- group had the shortest overall survival; C: in lung adenocarcinoma, the PD-L1-/CD45RO+ group had better overall survival than the other three groups
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