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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*
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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/ )
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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.
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Cancer Plus, Electronic ISSN: 2661-3840 Print ISSN: 2661-3832, Published by AccScience Publishing
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