Highly CD81-expressing stromal cells characterize a tumor-suppressive immune microenvironment in invasive breast cancer

Sep 22, 2026

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CD81 involvement in tumor progression is established, yet the functional role of stromal CD81 (sCD81) within the tumor microenvironment (TME) remains unclear. This study analyzed 462 primary invasive breast cancer samples and additional normal and in situ tissues collected from 2000–2013. Immunohistochemistry and spatial assays evaluated sCD81 expression, links to CAF subsets and immune components, clinicopathologic correlations, and survival. High sCD81 marked longer disease-free survival as an independent prognostic factor, defined by a CD34+ FAP-low PDGFRα-low phenotype and spatial proximity to tumor vasculature and CCL19-expressing cells.

LanguageEnglish

CategoryResearch & Report

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Pages16

Reading Time40 min

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Abstract

Background

Methods

Results

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Nakao et al. Breast Cancer Research (2026) 28:147 Breast Cancer Research [https://doi.org/10.1186/s13058-026-02326-4](https://doi.org/10.1186/s13058-026-02326-4) RESEARCH Open Access Highly CD81-expressing stromal cells characterize a tumor-suppressive immune microenvironment in invasive breast cancer Kenju Nakao 1,2†, Masayuki Komura 1,3*†, Shingo Inaguma4, Aya Nagano 1, Hiroyuki Kato 1, Aya Naiki-Ito 1, Tatsuya Toyama5 and Satoru Takahashi1 Abstract Background CD81, a member of the tetraspanin family, is implicated in tumor progression, and its elevated expression in tumor cells has been associated with poor prognosis across multiple cancers. However, the functional significance of CD81 within the stromal compartments of the tumor microenvironment (TME) remains unclear. This study investigated the clinical relevance and mechanistic role of stromal CD81 (sCD81) in invasive breast cancer. Methods A total of 462 human primary invasive breast cancer samples, along with 13 normal breast tissues and 10 ductal carcinoma in situ samples collected between 2000 and 2013, were analyzed. Immunohistochemistry and spatial analyses were used to evaluate sCD81 expression, and its association with cancer-associated fibroblast (CAF) subsets and immune components in theTME, as well as correlation with clinicopathological correlations and survival outcome. Results sCD81 expression was significantly higher in invasive breast cancer than in normal breast stromal tissue but did not differ across clinical subtypes. High sCD81 expression was associated with significantly longer diseasefree survival, and multivariate analysis identified sCD81 as an independent prognostic factor alongside nuclear grade, estrogen receptor status, and lymph node metastasis. Co-expression analyses demonstrated that sCD81-high stromal cells exhibited a CD34-positive, FAP-low, and PDGFRα-low phenotype, indicating that they are distinct from established CAF subtypes. Both sCD81 and podoplanin (PDPN) expression correlated with increased immune cell infiltration. However, PDPN-positive CAFs promoted an immunosuppressiveTME characterized by enrichment of regulatory T cells and M2-like macrophages, whereas CD81-high stromal cells did not exert such effects. Spatial analyses revealed that CD81-high stromal cells were preferentially localized near tumor vasculature and CCL19-expressing cells, suggesting a potential association with T-cell recruitment into the TME through CCL19-mediated mechanisms. †Kenju Nakao and Masayuki Komura have contributed equally to this work. *Correspondence: Masayuki Komura [komura@med.nagoya-cu.ac.jp](komura@med.nagoya-cu.ac.jp) Full list of author information is available at the end of the article © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-nc-nd/4.0/.) Nakao et al. Breast Cancer Research (2026) 28:147 Page 2 of 16 Conclusions These findings identify stromal

FAQs

What question does the study address about CD81 in breast cancer?

It tests the clinical relevance and mechanistic role of stromal CD81 (sCD81) in the tumor microenvironment of invasive breast cancer.

How were stromal CD81 expression and its immune effects assessed?

Researchers used immunohistochemistry and spatial analyses to measure sCD81, evaluate immune components, examine links to CAF subsets, and relate findings to survival.

What is the prognostic significance of high sCD81 in invasive breast cancer?

High sCD81 expression is associated with significantly longer disease-free survival and functions as an independent prognostic factor in multivariate analysis.

Sep 22, 2026

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