中国癌症杂志 ›› 2020, Vol. 30 ›› Issue (11): 849-857.doi: 10.19401/j.cnki.1007-3639.2020.11.001

• 论著 • 上一篇    下一篇

结直肠癌中LC3与不同表型肿瘤相关巨噬细胞的相关性及其临床意义

范守仁 1,2 ,吴淑华 3 ,李扬扬 3 ,许晓阳 3 ,何 双 3 ,温菲菲 3 ,刘 柳 3 ,郭宁杰 3 ,贾真真 3   

  1. 1. 滨州医学院临床医学院,山东 烟台 264003 ;
    2. 滨州市第二人民医院病理科,山东 滨州 256800 ;
    3. 滨州医学院附属医院病理科,山东 滨州 256600
  • 出版日期:2020-11-30 发布日期:2020-12-04
  • 通信作者: 吴淑华 E-mail: wsh6108@126.com
  • 基金资助:
    国家自然科学基金(81772637)。

The correlation between LC3 and tumor-associated macrophages in colorectal cancer and its clinical significance

FAN Shouren 1,2 , WU Shuhua 3 , LI Yangyang 3 , XU Xiaoyang 3 , HE Shuang 3 , WEN Feifei 3 , LIU Liu 3 , GUO Ningjie 3 , JIA Zhenzhen 3    

  1. 1. Clinical College, Binzhou Medical University, Yantai 264003, Shandong Province, China; 2. Department of Pathology, Binzhou Second People’s Hospital, Binzhou 256800, Shandong Province, China; 3. Department of Pathology, Binzhou Medical University Hospital, Binzhou 256600, Shandong Province, China
  • Online:2020-11-30 Published:2020-12-04
  • Contact: WU Shuhua E-mail: wsh6108@126.com

摘要: 背景与目的:肿瘤免疫逃逸成为免疫治疗的难点,而结直肠癌中过度自噬可引起肿瘤微环境内抗原物质的增加,进而诱导抗肿瘤免疫。通过检测自噬相关因子LC3、不同表型肿瘤相关巨噬细胞(tumor-associated macrophage,TAM)及其分泌产物在结直肠癌中的表达,探讨其相关性及临床意义。方法:采用免疫组织化学EnVision法检测滨州医学院附属医院病理科及滨州市第二人民医院病理科2013年1月—2014年12月存档的结直肠癌样本中LC3、CD16、CD163、IL-1、IL-10、TNF-α、TGF-β的表达,计数CD4 + 、CD8 + 、CD20 + 淋巴细胞及CD68 + 、CD16 + 、CD163 + 巨噬细胞,并分析其与临床病理学特征及预后的相关性。结果:自噬相关因子LC3、CD16、CD163在结直肠癌组织中的表达均高于癌旁正常黏膜组织(P<0.05)。LC3与M1型TAM及其在巨噬细胞中的占比均呈正相关,而与M2型TAM及其在巨噬细胞中的占比均呈负相关(P<0.05)。LC3、M1型TAM与IL-1、TNF-α的表达及CD4 + 、CD8 + 、CD20 + 淋巴细胞的浸润量呈正相关;而M2型TAM与IL-10、TGF-β的表达呈正相关,而与CD4 + 、CD8 + 、CD20 + 淋巴细胞的浸润量呈负相关(P<0.05)。LC3、CD16、CD163与肿瘤直径、浸润深度及淋巴结转移密切相关(P<0.05)。Kaplan-Meier及COX回归模型分析显示,LC3、CD16、CD163及淋巴结转移与结直肠癌患者预后密切相关,是结直肠癌预后的独立危险因素。结论:结直肠癌中LC3的表达增加与M1型TAM极化、肿瘤进展密切相关,提示患者预后不良。结直肠癌中自噬水平的增高可诱导巨噬细胞募集并向M1型TAM极化,进而诱导免疫细胞聚集,因此调控自噬可成为诱导结直肠癌中TAM极化、增强抗肿瘤免疫的新思路。

关键词: 结直肠癌, 自噬, 肿瘤相关巨噬细胞, LC3, 肿瘤微环境

Abstract: Background and purpose: Tumor immune escape has become the difficulty of immunotherapy. In colorectal cancer, active autophagy can increase antigen in tumor microcirculation and then induce anti-tumor immunity. This study aimed to detect the expressions of LC3, tumor-associated macrophage (TAM) and their products in colorectal cancer, and to explore the influence of LC3 on tumor microenvironment and its clinical significance. Methods: Immunohistochemical analysis was used to detect the expressions of LC3, CD16, CD163, CD4, CD8, CD20, CD68, IL-1, IL-10, TNF-α and TGF-β in colorectal cancer samples archived in the department of pathology, Binzhou Medical University Hospital and department of pathology, Binzhou Second People’s Hospital from Jan. 2013 to Dec. 2014, and their correlations with clinicopathological features and prognosis were analyzed. Results: The expressions of LC3, CD16 and CD163 were higher in colorectal cancer than in adjacent normal colon tissues (P<0.05). The expression of LC3 was positively correlated with the infiltration of M1 TAM, but negatively correlated with the infiltration of M2 TAM (P<0.05). The expressions of LC3 and M1 TAM were positively correlated with IL-1, TNF-α and the infiltration of CD4 + , CD8 + and CD20 + lymphocytes, while the expression of M2 TAM was positively correlated with IL-10 and TGF-β, but negatively correlated with the infiltration of CD4 + , CD8 + and CD20 + lymphocytes (P<0.05). The expressions of LC3, CD16 and CD163 were closely related to tumor size, invasion and lymph node metastasis (P<0.05). Kaplan-Meier and COX regression model analyses showed that the expression levels of LC3, CD16 and CD163 and lymph node metastasis were closely related to the prognosis of colorectal cancer patients, and were independent risk factors for the prognosis of colorectal cancer. Conclusion: The increase of autophagy in colorectal cancer can induce macrophage recruitment and polarization of TAM into M1 phenotype, and then induces immune cell aggregation. Regulating autophagy can be a new way to induce polarization of TAM and enhance anti-tumor immunity in colorectal cancer.

Key words: Colorectal cancer, Autophagy, Tumor-associated macrophage, LC3, Tumor microenvironment