Correlation of LC3 and the recruitment of dendritic cell and the formation of TLS in colorectal cancer and its clinical significance

Han WU; Lei XU; Miaomiao WANG; Ruizhe ZHANG; Xiaoyang XU; Ningjie GUO; Shuhua WU

doi:10.19401/j.cnki.1007-3639.2023.09.002

您当前的位置：

首页 >

文章列表页 >

Correlation of LC3 and the recruitment of dendritic cell and the formation of TLS in colorectal cancer and its clinical significance

Article | 更新时间：2025-12-31

- Correlation of LC3 and the recruitment of dendritic cell and the formation of TLS in colorectal cancer and its clinical significance
- China Oncology Vol. 33, Issue 9, Pages: 818-828(2023)
- 作者机构：
  
  滨州医学院附属医院病理科，山东滨州 256600
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2023.09.002
  CLC： R735.3+5；R735.3+7
- Received：18 July 2023，
  
  Revised：2023-09-12，
  
  Published：30 September 2023
- 稿件说明：
移动端阅览
Han WU, Lei XU, Miaomiao WANG, et al. Correlation of LC3 and the recruitment of dendritic cell and the formation of TLS in colorectal cancer and its clinical significance[J]. China Oncology, 2023, 33(9): 818-828.
DOI：

Han WU, Lei XU, Miaomiao WANG, et al. Correlation of LC3 and the recruitment of dendritic cell and the formation of TLS in colorectal cancer and its clinical significance[J]. China Oncology, 2023, 33(9): 818-828. DOI： 10.19401/j.cnki.1007-3639.2023.09.002.

摘要

背景与目的：

肿瘤细胞免疫逃逸是肿瘤治疗中的难点，而肿瘤细胞中自噬过度激活会引起肿瘤细胞表面抗原的增加，参与抗肿瘤免疫。本研究通过临床样本检测结直肠癌中自噬关键因子微管相关蛋白轻链3（light chain 3，LC3）表达、成熟树突状细胞（mature dendritic cell，mDC）数目及三级淋巴结构（tertiary lymphoid structure，TLS）的形成，探讨其相关性及临床意义，旨在为增强抗肿瘤免疫治疗提供新思路。

方法：

采用免疫组织化学EnVision法检测2016年1月—2017年6月滨州医学院附属医院收治的经手术切除的179例T

期高危及T

期结直肠癌患者的癌组织及癌旁组织中LC3、DC-lamp的表达和TLS的形成。采用蛋白质印迹法（Western blot）及实时荧光定量聚合酶链反应（real-time fluorescence quantitative polymerase chain reaction，RTFQ-PCR）检测TLS

及TLS

结直肠癌组织中LC3、NY-ESO-2、淋巴毒素β（lymphotoxin-beta，LTβ）、CC族趋化因子配体21（CC chemokine ligand 21，CCL21）、CXC族趋化因子配体13（CXC chemokine ligand 13，CXCL13）及白细胞介素17（interleukin-17，IL-17）的表达，分析其相关性及临床意义。采用log-rank检验比较组间预后差异，采用COX比例风险回归模型进行多因素生存分析。

结果：

结直肠癌组织中LC3、DC-lamp的表达量均高于癌旁组织（

0.05），LC3与DC-lamp的表达呈正相关（

0.05）。TLS

组中LC3、NY-ESO-2、LTβ、CXCL13及CCL21的蛋白水平及mRNA表达均高于TLS

组（

0.05），而IL-17的表达量则低于TLS

组（

0.05），LC3表达与TLS/生发中心（germinal center，GC）

、TLS/GC

两亚型均呈正相关（

0.05），且与NY-ESO-2、LTβ、CXCL13及CCL21的表达呈正相关（

0.05）。DC-lamp在TLS/GC

和TLS/GC

亚型组中的表达量均高于其余两亚组（

0.05），且呈正相关（

0.05）。Log-rank检验及COX比例风险回归模型显示，结直肠癌中LC3、DC-lamp、TLS及淋巴结转移与结直肠癌患者的预后密切相关，且均是结直肠癌预后的独立危险因素。

结论：

结直肠癌中LC3异常表达可通过增加表面抗原激活mDC，进而募集淋巴细胞，促进TLS的形成与成熟，最终影响患者的预后。

Abstract

Background and purpose:

It has been recognized as a complex problem in tumor therapy to deal with the tumor immune escape

and over-activated autophagy can cause the increase of tumor surface antigen

which participates in anti-tumor immunity. In this study

the expressions of microtubule-associated protein light chain 3 (LC

mature dendritic cell (mDC) and the formation of tertiary lymphoid structure (TLS)

an essential autophagy factor in colorectal cancer

were detected in clinical samples. The results had important clinical implications and provided new insights for enhancing anti-tumor immunity.

Methods:

Immunohistochemical EnVision method was used to detect the expressions of LC3

DC-lamp and the formation of TLS in cancer tissues and normal mucosal tissues of 179 patients with T

stage high-risk and T

stage colorectal cancer who underwent surgical resection at Binzhou Medical University Hospital from January 2016 to June 2017. Western blot and real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) were used to detect the expressions of LC3

NY-ESO-2

lymphotoxin-beta (LTβ)

CC chemokine ligand 21 (CCL21)

CXC chemokine ligand 13 (CXCL13) and interleukin-17 (IL-17) in TLS

and TLS

colorectal cancer tissues. Then the correlation and clinical significance were analyzed. Log-rank test was used to compare the prognostic differences between groups

and COX proportional risk regression model was used for multivariate survival analysis.

Results:

Clinical samples showed that the expressions of LC3 and DC-lamp were higher in colorectal cancer tissues than in normal mucosa tissues (

0.05)

and the expressions of LC3 and DC-lamp were positively correlated (

0.05). The protein and mRNA expressions of LC3

NY-ESO-2

LTβ

CXCL13 and CCL21 were higher in TLS

group than in TLS

group. The expression of IL-17 was higher in the TLS

group than in the TLS

group (

0.05). The expression of LC3 was positively correlated with TLS/germinal center (GC)

and TLS/GC

subtypes and positively correlated with the expression of NY-ESO-2

LTβ

CXCL13 and CCL21 (

0.05). The expression of DC-lamp was higher in TLS/GC

and TLS/GC

subtype groups than in the other two subgroups (

0.05)

and there was a positive correlation. Kaplan-Meier and COX regression models showed that LC3

DC-lamp

TLS and lymph node metastasis were closely related to the prognosis of patients with colorectal cancer

and they were independent risk factors for the prognosis of colorectal cancer.

Conclusion:

The abnormal expression of LC3 in colorectal cancer can activate mDC to recruit lymphocytes and promote the expression and maturation of TLS

ultimately affecting the prognosis of patients.

关键词

Keywords

references

SUNG H , FERLAY J , SIEGEL R L , et al . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for36 cancers in 185 countries [J ] . CA Cancer J Clin , 2021 , 71 ( 3 ): 209 - 249 . DOI: 10.3322/caac.v71.3 http://doi.org/10.3322/caac.v71.3 https://acsjournals.onlinelibrary.wiley.com/toc/15424863/71/3 https://acsjournals.onlinelibrary.wiley.com/toc/15424863/71/3

SCHUMACHER T N , THOMMEN D S . Tertiary lymphoid structures in cancer [J ] . Science , 2022 , 375 ( 6576 ): eabf9419 . DOI: 10.1126/science.abf9419 http://doi.org/10.1126/science.abf9419 https://www.science.org/doi/10.1126/science.abf9419 https://www.science.org/doi/10.1126/science.abf9419

DI CARO G , BERGOMAS F , GRIZZI F , et al . Occurrence of tertiary lymphoid tissue is associated with T-cell infiltration and predicts better prognosis in early-stage colorectal cancers [J ] . Clin Cancer Res , 2014 , 20 ( 8 ): 2147 - 2158 . DOI: 10.1158/1078-0432.CCR-13-2590 http://doi.org/10.1158/1078-0432.CCR-13-2590

范守仁 , 吴淑华 , 李扬扬 , 等 . 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 [J ] . 中国癌症杂志 , 2020 , 30 ( 11 ): 849 - 857 .

FAN S R , WU S H , LI Y Y , et al . The correlation between LC3 and tumor-associated macrophages in colorectal cancer and its clinical significance [J ] . China Oncol , 2020 , 30 ( 11 ): 849 - 857 .

WHO Classification of Tumours Editorial Board . WHO classification of tumours of digestive system [M ] . Lyon : IARC Press , 2019 .

TANAKA T , MASUDA A , INOUE J , et al . Integrated analysis of tertiary lymphoid structures in relation to tumor-infiltrating lymphocytes and patient survival in pancreatic ductal adenocarcinoma [J ] . J Gastroenterol , 2023 , 58 ( 3 ): 277 - 291 . DOI: 10.1007/s00535-022-01939-8 http://doi.org/10.1007/s00535-022-01939-8

XIA H J , GREEN D R , ZOU W P . Autophagy in tumour immunity and therapy [J ] . Nat Rev Cancer , 2021 , 21 ( 5 ): 281 - 297 . DOI: 10.1038/s41568-021-00344-2 http://doi.org/10.1038/s41568-021-00344-2

ZHAO Y , CODOGNO P , ZHANG H . Machinery, regulation and pathophysiological implications of autophagosome maturation [J ] . Nat Rev Mol Cell Biol , 2021 , 22 ( 11 ): 733 - 750 . DOI: 10.1038/s41580-021-00392-4 http://doi.org/10.1038/s41580-021-00392-4

MÜNZ C . Canonical and non-canonical functions of the autophagy machinery in MHC restricted antigen presentation [J ] . Front Immunol , 2022 , 13 : 868888 . DOI: 10.3389/fimmu.2022.868888 http://doi.org/10.3389/fimmu.2022.868888 https://www.frontiersin.org/articles/10.3389/fimmu.2022.868888/full https://www.frontiersin.org/articles/10.3389/fimmu.2022.868888/full

ROMAO S , MÜNZ C . LC3-associated phagocytosis [J ] . Autophagy , 2014 , 10 ( 3 ): 526 - 528 . DOI: 10.4161/auto.27606 http://doi.org/10.4161/auto.27606

JIN Y , SUN C J , FENG L Q , et al . Regulation of SIV antigen-specific CD4 + T cellular immunity via autophagosome-mediated MHC Ⅱ molecule-targeting antigen presentation in mice [J ] . PLoS One , 2014 , 9 ( 3 ): e93143 . DOI: 10.1371/journal.pone.0093143 http://doi.org/10.1371/journal.pone.0093143 https://dx.plos.org/10.1371/journal.pone.0093143 https://dx.plos.org/10.1371/journal.pone.0093143

SHANTHA KUMARA H M , GRIECO M J , CABALLERO O L , et al . MAGE-A3 is highly expressed in a subset of colorectal cancer patients [J ] . Cancer Immun , 2012 , 12 : 16 .

刘梦瑶 , 吴淑华 , 温菲菲 , 等 . 结直肠癌中LC3与CD4 + 、CD8 + 、CD68 + 免疫细胞浸润的相关性及其临床意义 [J ] . 临床与实验病理学杂志 , 2018 , 34 ( 2 ): 124 - 131 .

LIU M Y , WU S H , WEN F F , et al . Correlation of LC3 and CD4+, CD8+ and CD68+ cell infiltration in colorectal cancer and its clinical significance [J ] . Chin J Clin Exp Pathol , 2018 , 34 ( 2 ): 124 - 131 .

MERAD M , SATHE P , HELFT J , et al . The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting [J ] . Annu Rev Immunol , 2013 , 31 : 563 - 604 . DOI: 10.1146/annurev-immunol-020711-074950 http://doi.org/10.1146/annurev-immunol-020711-074950

MILDNER A , JUNG S . Development and function of dendritic cell subsets [J ] . Immunity , 2014 , 40 ( 5 ): 642 - 656 . DOI: 10.1016/j.immuni.2014.04.016 http://doi.org/10.1016/j.immuni.2014.04.016

COLLIN M , BIGLEY V . Human dendritic cell subsets: an update [J ] . Immunology , 2018 , 154 ( 1 ): 3 - 20 . DOI: 10.1111/imm.12888 http://doi.org/10.1111/imm.12888

FRIDMAN W H , MEYLAN M , PETITPREZ F , et al . B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome [J ] . Nat Rev Clin Oncol , 2022 , 19 ( 7 ): 441 - 457 . DOI: 10.1038/s41571-022-00619-z http://doi.org/10.1038/s41571-022-00619-z

YAMAMOTO K , VENIDA A , YANO J , et al . Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I [J ] . Nature , 2020 , 581 ( 7806 ): 100 - 105 . DOI: 10.1038/s41586-020-2229-5 http://doi.org/10.1038/s41586-020-2229-5

TIAN Y , KUO C F , SIR D , et al . Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis [J ] . Cell Death Differ , 2015 , 22 ( 6 ): 1025 - 1034 . DOI: 10.1038/cdd.2014.201 http://doi.org/10.1038/cdd.2014.201

MAOZ A , DENNIS M , GREENSON J K . The Crohn’s-like lymphoid reaction to colorectal cancer-tertiary lymphoid structures with immunologic and potentially therapeutic relevance in colorectal cancer [J ] . Front Immunol , 2019 , 10 : 1884 . DOI: 10.3389/fimmu.2019.01884 http://doi.org/10.3389/fimmu.2019.01884 https://www.frontiersin.org/article/10.3389/fimmu.2019.01884/full https://www.frontiersin.org/article/10.3389/fimmu.2019.01884/full

SAUTÈS-FRIDMAN C , PETITPREZ F , CALDERARO J , et al . Tertiary lymphoid structures in the era of cancer immunotherapy [J ] . Nat Rev Cancer , 2019 , 19 ( 6 ): 307 - 325 . DOI: 10.1038/s41568-019-0144-6 http://doi.org/10.1038/s41568-019-0144-6

WANG B , LIU J , HAN Y , et al . The presence of tertiary lymphoid structures provides new insight into the clinicopathological features and prognosis of patients with breast cancer [J ] . Front Immunol , 2022 , 13 : 868155 . DOI: 10.3389/fimmu.2022.868155 http://doi.org/10.3389/fimmu.2022.868155 https://www.frontiersin.org/articles/10.3389/fimmu.2022.868155/full https://www.frontiersin.org/articles/10.3389/fimmu.2022.868155/full

SILIŅA K , SOLTERMANN A , ATTAR F M , et al . Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma [J ] . Cancer Res , 2018 , 78 ( 5 ): 1308 - 1320 . DOI: 10.1158/0008-5472.CAN-17-1987 http://doi.org/10.1158/0008-5472.CAN-17-1987

DING G Y , MA J Q , YUN J P , et al . Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma [J ] . J Hepatol , 2022 , 76 ( 3 ): 608 - 618 . DOI: 10.1016/j.jhep.2021.10.030 http://doi.org/10.1016/j.jhep.2021.10.030 https://linkinghub.elsevier.com/retrieve/pii/S0168827821021784 https://linkinghub.elsevier.com/retrieve/pii/S0168827821021784

WEINSTEIN A M , CHEN L , BRZANA E A , et al . Tbet and IL-36γ cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment [J ] . OncoImmunology , 2017 , 6 ( 6 ): e1322238 . DOI: 10.1080/2162402X.2017.1322238 http://doi.org/10.1080/2162402X.2017.1322238 https://www.tandfonline.com/doi/full/10.1080/2162402X.2017.1322238 https://www.tandfonline.com/doi/full/10.1080/2162402X.2017.1322238

HALLE S , DUJARDIN H C , BAKOCEVIC N , et al . Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells [J ] . J Exp Med , 2009 , 206 ( 12 ): 2593 - 2601 . DOI: 10.1084/jem.20091472 http://doi.org/10.1084/jem.20091472 https://rupress.org/jem/article/206/12/2593/40325/Induced-bronchus-associated-lymphoid-tissue-serves https://rupress.org/jem/article/206/12/2593/40325/Induced-bronchus-associated-lymphoid-tissue-serves

COLBECK E J , AGER A , GALLIMORE A , et al . Tertiary lymphoid structures in cancer: drivers of antitumor immunity, immunosuppression, or bystander sentinels in disease? [J ] . Front Immunol , 2017 , 8 : 1830 . DOI: 10.3389/fimmu.2017.01830 http://doi.org/10.3389/fimmu.2017.01830

J GUNDERSON A , RAJAMANICKAM V , BUI C , et al . Germinal center reactions in tertiary lymphoid structures associate with neoantigen burden, humoral immunity and long-term survivorship in pancreatic cancer [J ] . Oncoimmunology , 2021 , 10 ( 1 ): 1900635 . DOI: 10.1080/2162402X.2021.1900635 http://doi.org/10.1080/2162402X.2021.1900635 https://www.tandfonline.com/doi/full/10.1080/2162402X.2021.1900635 https://www.tandfonline.com/doi/full/10.1080/2162402X.2021.1900635

WANG Q Y , SHEN X F , AN R , et al . Peritumoral tertiary lymphoid structure and tumor stroma percentage predict the prognosis of patients with non-metastatic colorectal cancer [J ] . Front Immunol , 2022 , 13 : 962056 . DOI: 10.3389/fimmu.2022.962056 http://doi.org/10.3389/fimmu.2022.962056 https://www.frontiersin.org/articles/10.3389/fimmu.2022.962056/full https://www.frontiersin.org/articles/10.3389/fimmu.2022.962056/full

LI S , LIN Z , ZHENG W , et al . IL-17A inhibits autophagic activity of HCC cells by inhibiting the degradation of Bcl2 [J ] . Biochem Biophys Res Commun , 2019 , 509 ( 1 ): 194 - 200 . DOI: 10.1016/j.bbrc.2018.12.103 http://doi.org/10.1016/j.bbrc.2018.12.103 https://linkinghub.elsevier.com/retrieve/pii/S0006291X18327529 https://linkinghub.elsevier.com/retrieve/pii/S0006291X18327529

DIEU-NOSJEAN M C , GIRALDO N A , KAPLON H , et al . Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers [J ] . Immunol Rev , 2016 , 271 ( 1 ): 260 - 275 . DOI: 10.1111/imr.2016.271.issue-1 http://doi.org/10.1111/imr.2016.271.issue-1 https://onlinelibrary.wiley.com/toc/1600065x/271/1 https://onlinelibrary.wiley.com/toc/1600065x/271/1

CALDERARO J , PETITPREZ F , BECHT E , et al . Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma [J ] . J Hepatol , 2019 , 70 ( 1 ): 58 - 65 . DOI: S0168-8278(18)32373-0 http://doi.org/S0168-8278(18)32373-0

ALLEMANI C , MATSUDA T , DI CARLO V , et al . Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries [J ] . Lancet , 2018 , 391 ( 10125 ): 1023 - 1075 . DOI: 10.1016/S0140-6736(17)33326-3 http://doi.org/10.1016/S0140-6736(17)33326-3 https://linkinghub.elsevier.com/retrieve/pii/S0140673617333263 https://linkinghub.elsevier.com/retrieve/pii/S0140673617333263

Views

2854

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Experimental study on influence of autophagy on DPD expression and its effect on chemotherapy with 5-FU in colorectal cancer

Correlations between expressions of DPD, LC3 and P62 in colorectal cancer and their clinical significance

Research progress and clinical significance of breast cancer heterogeneity

The clinical significance of thyroglobulin antibody measurement in 131I therapy of differentiated thyroid carcinoma

Detection of HPV in peripheral blood and its clinical significance

Related Author

Shuhua WU

Lizhen LU

Zhongze CUI

Shuang HE

Feifei WEN

Yangyang LI

Xiaoyang XU

Shuhua WU

Related Institution

南京医科大学附属上海一院临床医学院肿瘤科

上海交通大学附属胸科医院心内科

中国医学科学院北京协和医学院北京协和医院核医学科

复旦大学附属肿瘤医院妇瘤科，复旦大学上海医学院肿瘤学系

中南大学公共卫生学院

AI问答

⁰