AccScience Publishing / CP / Online First /
Submit to CP
Cite this article
11
Download
61
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Effects of Wnt signaling pathway on tertiary lymphoid structure in the immune microenvironment of colorectal cancer with different MMR subtypes

Huijing Feng1† ,  Fei Han2† ,  Huiru Xu1† ,  Siyuan Zhang3,4,5,6,7,8† ,  Qiuru Zhou3,4,5,6,7,8,9† ,  Yanan Ma1 ,  Lin Wang10 ,  Xuena Yang8 ,  Feng Wei8,11 ,  Hua Zhao8,11* ,  Xiubao Ren8,11,12*
Show Less
1 Department of Thoracic Oncology, Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
2 Department of Head and Neck Surgery, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
3 Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
4 National Clinical Research Center for Cancer, Tianjin, China
5 Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
6 Tianjin’s Clinical Research Center for Cancer, Tianjin, China
7 Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
8 Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
9 Wenzhou Central Hospital, Wenzhou, Zhejiang, China
10 Department of General Surgery, Shanxi Bethune Hospital, Taiyuan, Shanxi, China
11 Haihe Laboratory of Cell Ecosystem, Tianjin, China
12 Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
CP, 4604
Submitted: 20 August 2024 | Accepted: 31 October 2024 | Published: 28 November 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
Cite
XML
Abstract

Tertiary lymphoid structure (TLS) and tumor-resident memory T cells (TRM), as the important components of tumor microenvironment, play key roles in the anti-tumor immunity and therapy functions in cancer patients. However, the TRM and TLS distribution in colorectal cancer (CRC) patients with different mismatch repair (MMR) subtypes and Wnt pathway activation, as well as their relationship, remain underexplored. In this study, we evaluated the MMR subtypes and Wnt/β-catenin using immunohistochemical staining and analyzed their relationship in a sample of 117 cases. We detected TLS distribution, quantity, and maturity in CRC samples of different MMR subtypes by multiple immunofluorescence staining and analyzed its correlation with Wnt/β-catenin pathway. We then detected TRM expression inside and outside the TLS and tumor tissues in 34 CRC samples by means of multiple immunofluorescence staining and analyzed its correlation with Wnt/β-catenin pathway. Our study showed that the proportion of β-catenin in MMR-proficient (pMMR) CRC was significantly higher than that in MMR-deficient (dMMR) CRC. The peritumoral and intratumoral TLS quantity in dMMR group was obviously higher than that in high and low pMMR-β-catenin expression groups. The intratumoral TLS quantity negatively correlated with β-catenin expression in dMMR group and low pMMR-β-catenin group, respectively. In addition, the positive rate and density of CD8+TRM in the TLS were significantly higher than that outside. The positive rate and density of CD8+TRM of tumor tissues in dMMR CRC were higher than those in pMMR CRC. Furthermore, the positive rate of CD8+TRM in tumor tissues of CRC patients in the low β-catenin expression group was higher than that in the high β-catenin expression group. Taken together, TLS and TRM cells in CRC with different Wnt classical pathway activation states and MMR subtypes could serve as a potential biomarker for the prediction of the efficacy of immunotherapy in CRC patients.

Keywords
Colorectal cancer
Mismatch repair
Wnt signaling pathway
Tertiary lymphatic structure
Tissue-resident memory T cells
Funding
None.
Conflict of interest
Huijing Feng is an Editorial Board Member of this journal but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
References
  1. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394(10207):1467-1480. doi: 10.1016/S0140-6736(19)32319-0

 

  1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660

 

  1. Li J, Wu C, Hu H, et al. Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer. Cancer Cell. 2023;41(6):1152-1169.e7. doi: 10.1016/j.ccell.2023.04.011

 

  1. Sautès-Fridman C, Petitprez F, Calderaro J, Fridman WH. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019;19(6):307-325. doi: 10.1038/s41568-019-0144-6

 

  1. Wang J, Jiang D, Zheng X, et al. Tertiary lymphoid structure and decreased CD8+ T cell infiltration in minimally invasive adenocarcinoma. iScience. 2022;25(3):103883. doi: 10.1016/j.isci.2022.103883

 

  1. Tokunaga R, Naseem M, Lo JH, et al. B cell and B cell-related pathways for novel cancer treatments. Cancer Treat Rev. 2019;73:10-19. doi: 10.1016/j.ctrv.2018.12.001

 

  1. Hayashi Y, Makino T, Sato E, et al. Density and maturity of peritumoral tertiary lymphoid structures in oesophageal squamous cell carcinoma predicts patient survival and response to immune checkpoint inhibitors. Br J Cancer. 2023;128(12):2175-2185. doi: 10.1038/s41416-023-02235-9

 

  1. Zhou L, Xu B, Liu Y, Wang Z. Tertiary lymphoid structure signatures are associated with survival and immunotherapy response in muscle-invasive bladder cancer. Oncoimmunology. 2021;10(1):1915574. doi: 10.1080/2162402X.2021.1915574

 

  1. Cabrita R, Lauss M, Sanna A, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020;577(7791):561-565. doi: 10.1038/s41586-019-1914-8

 

  1. Zhan Z, Shi-Jin L, Yi-Ran Z, et al. High endothelial venules proportion in tertiary lymphoid structure is a prognostic marker and correlated with anti-tumor immune microenvironment in colorectal cancer. Ann Med. 2023;55(1):114-126. doi: 10.1080/07853890.2022.2153911

 

  1. Feng H, Zhang S, Zhou Q, et al. Intratumor tertiary lymphatic structure evaluation predicts the prognosis and immunotherapy response of patients with colorectal cancer. Front Immunol. 2024;15:1302903. doi: 10.3389/fimmu.2024.1302903

 

  1. Savas P, Virassamy B, Ye C, et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med. 2018;24(7):986-993. doi: 10.1038/s41591-018-0078-7

 

  1. Banchereau R, Chitre AS, Scherl A, et al. Intratumoral CD103+ CD8+ T cells predict response to PD-L1 blockade. J Immunother Cancer. 2021;9(4):e002231. doi: 10.1136/jitc-2020-002231

 

  1. Hu C, You W, Kong D, et al. Tertiary lymphoid structure-associated B cells enhance CXCL13+CD103+CD8+ tissue-resident memory T-Cell response to programmed cell death protein 1 blockade in cancer immunotherapy. Gastroenterology. 2024;166(6):1069-1084. doi: 10.1053/j.gastro.2023.10.022

 

  1. Workel HH, Lubbers JM, Arnold R, et al. A Transcriptionally distinct CXCL13+CD103+CD8+ T-cell population is associated with B-cell recruitment and neoantigen load in human cancer. Cancer Immunol Res. 2019;7(5):784-796. doi: 10.1158/2326-6066.CIR-18-0517

 

  1. Zhao H, Wang H, Zhao Y, Sun Q, Ren X. Tumor-resident T cells, associated with tertiary lymphoid structure maturity, improve survival in patients with stage III lung adenocarcinoma. Front Immunol. 2022;13:877689. doi: 10.3389/fimmu.2022.877689

 

  1. Mori T, Tanaka H, Suzuki S, et al. Tertiary lymphoid structures show infiltration of effective tumor-resident T cells in gastric cancer. Cancer Sci. 2021;112(5):1746-1757. doi: 10.1111/cas.14888

 

  1. Zhao H, Ming T, Tang S, et al. Wnt signaling in colorectal cancer: Pathogenic role and therapeutic target. Mol Cancer. 2022;21(1):144. doi: 10.1186/s12943-022-01616-7

 

  1. Tang Q, Chen J, Di Z, et al. TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer. J Exp Clin Cancer Res. 2020;39(1):232. doi: 10.1186/s13046-020-01690-z

 

  1. Dong S, Liang S, Cheng Z, et al. ROS/PI3K/Akt and Wnt/ β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer. J Exp Clin Cancer Res. 2022;41(1):15. doi: 10.1186/s13046-021-02229-6

 

  1. Tran TQ, Hanse EA, Habowski AN, et al. α-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer. Nat Cancer. 2020;1(3):345-358. doi: 10.1038/s43018-020-0035-5

 

  1. Qiu Q, Tan D, Chen Q, et al. Clinical implications of PD-L1 expression and pathway-related molecular subtypes in advanced Asian colorectal cancer patients. Am J Cancer Res. 2024;14(2):796-808. doi: 10.62347/FSSF9938

 

  1. Tang Y, Nan N, Gui C, Zhou X, Jiang W, Zhou X. Blockage of PD-L1 by FERMT3-mediated Wnt/β-catenin signalling regulates chemoresistance and immune evasion of colorectal cancer cells. Clin Exp Pharmacol Physiol. 2022;49(9):988-997. doi: 10.1111/1440-1681.13685

 

  1. Scholtka B, Schneider M, Melcher R, et al. A gene marker panel covering the Wnt and the Ras-Raf-MEK-MAPK signalling pathways allows to detect gene mutations in 80% of early (UICC I) colon cancer stages in humans. Cancer Epidemiol. 2009;33(2):123-129. doi: 10.1016/j.canep.2009.05.001

 

  1. Raman R, Kotapalli V, Adduri R, et al. Evidence for possible non-canonical pathway(s) driven early-onset colorectal cancer in India. Mol Carcinog. 2014;53(Suppl 1):E181-E186. doi: 10.1002/mc.21976

 

  1. Qi L, Chen J, Zhou B, et al. HomeoboxC6 promotes metastasis by orchestrating the DKK1/Wnt/β-catenin axis in right-sided colon cancer. Cell Death Dis. 2021;12(4):337. doi: 10.1038/s41419-021-03630-x

 

  1. Fahrer AM, Bazan JF, Papathanasiou P, Nelms KA, Goodnow CC. A genomic view of immunology. Nature. 2001;409(6822):836-838. doi: 10.1038/35057020

 

  1. Li B, Wu S, Qiu Z, et al. The predictive value and correlation of β-catenin, CMTM6, and PD-L1 expression in colorectal cancer. Neoplasma. 2022;69(3):691-699. doi: 10.4149/neo_2022_210809N1122

 

  1. Morcrette G, Hirsch TZ, Badour E, et al. APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. Oncoimmunology. 2019;8(6):e1583547. doi: 10.1080/2162402X.2019.1583547

 

  1. Jin K, Yu Y, Zeng H, et al. CD103+CD8+ tissue-resident memory T cell infiltration predicts clinical outcome and adjuvant therapeutic benefit in muscle-invasive bladder cancer. Br J Cancer. 2022;126(11):1581-1588. doi: 10.1038/s41416-022-01725-6

 

  1. Kim HD, Jeong S, Park S, et al. Implication of CD69+ CD103+ tissue-resident-like CD8+ T cells as a potential immunotherapeutic target for cholangiocarcinoma. Liver Int. 2021;41(4):764-776. doi: 10.1111/liv.14814

 

  1. Boudousquié C, Danilo M, Pousse L, et al. Differences in the transduction of canonical Wnt signals demarcate effector and memory CD8 T cells with distinct recall proliferation capacity. J Immunol. 2014;193(6):2784-2791. doi: 10.4049/jimmunol.1400465
Next article in this issue
Share
Back to top
Cancer Plus, Electronic ISSN: 2661-3840 Print ISSN: 2661-3832, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept