ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1649078
This article is part of the Research TopicExploring the Breast Tumor Microenvironment: Association to Metastasis, Novel Risk Factors and Novel Treatments and Immunotherapies: Volume II.View all 12 articles
CD155-TIGIT/CD96/CD226 immune checkpoint axis interacting with tumor-infiltrating lymphocytes to exhibit diverse prognostic effects on breast cancer: a cohort study
Provisionally accepted
Xin Ou1
Junyu Yin1
Feng Shi2
Yanjie Zhao3
Quan Zhou4Keyu Yuan5Shuzhen Lyu5Jiangping Wu1
Li Yanping5
Qingkun Song1*- 1Department of Clinical Epidemiology, Beijing You'an Hospital Affiliated to Capital Medical University, Beijing, China
- 2Department of Pathology, Beijing Shijitan Hospital Capital Medical University, Beijing, China
- 3Department of Medical Oncology, Beijing Shijitan Hospital Capital Medical University, Beijing, China
- 4Department of Pathology, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China
- 5Department of Breast Surgery, Beijing Shijitan Hospital Capital Medical University, Beijing, China
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Abstract Background: CD155, an immune checkpoint molecule interacted with receptors of TIGIT/CD96/ CD226 to exhibit co-inhibitory and co-stimulatory modulation on tumor immune microenvironment. Nevertheless, the exploration of collectively prognostic effect of these four molecules on breast cancer (BC) was limited. This study aimed to investigate the prognosis effect of CD155-TIGIT/CD96/CD226 complex in BC. Methods: CD155-TIGIT/CD96/CD226 expression was evaluated by immunohistochemistry in tumor microenvironment (TME) by pathological professionals and the associations with clinical characteristics and prognosis were investigated under a cohort study design. Results: CD155 was detected on TME tumor cells (TC) and TIGIT/CD96/CD226 were detected on both TC and stromal tumor-infiltrated lymphocytes (TILs). The four molecules showed significant correlation with clinicopathological characteristics and prognosis. High CD155 was associated with relapse (HR=2.21, 95%CI:1.18-4.13) and death (HR=2.57, 95%CI:1.29-5.10). High expression of CD226 (HR=1.79, 95%CI:1.03-3.11) and CD96 (HR=2.65, 95%CI:1.09-6.44) on TC was correlated with high risk of relapse. High expression of TIGIT on TILs was related to poor prognosis of relapse (HR=2.06, 95%CI:1.02-4.14), while the expression on TC was a protective factor for relapse (HR=0.45, 95%CI:0.24-0.83) and death (HR=0.32, 95%CI:0.16-0.66). Additionally, tumoral and stromal expression of these biomarkers interacted with TME infiltration of stromal TILs to exhibit the diverse prognosis effect. Conclusion: The CD155-CD226/TIGIT/CD96 immune checkpoint complex expressed on both TME TC and TILs, and interacted with TILs to exhibit diverse prognosis effect on BC. The immunotherapy against these checkpoint proteins should check the expression on both TC and TILs and further studies should explore the molecule complex collectively for comprehensive prediction of BC prognosis.
Keywords: CD155-TIGIT/CD226/CD96 immune checkpoint molecules, prognosis, breast cancer, tumor cells, Tumor-infiltrating lymphocytes, Tumor Microenvironment
Received: 18 Jun 2025; Accepted: 06 Oct 2025.
Copyright: © 2025 Ou, Yin, Shi, Zhao, Zhou, Yuan, Lyu, Wu, Yanping and Song. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Qingkun Song, songqingkun@ccmu.edu.cn
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