Clinical significance of CD155 expression and correlation with immune cell infiltration in triple-negative breast cancer

Introduction

According to the latest cancer statistics, breast cancer remains the most prevalent malignancy among women worldwide (1). Triple-negative breast cancer (TNBC), a distinct subtype characterized by the absence of hormone receptor (progesterone and estrogen) expression and human epidermal growth factor receptor 2 (HER2) over expression, accounts for 10–20% of all breast cancer cases (2). This subtype is notably aggressive, exhibiting a high propensity for recurrence and metastasis, and is associated with a comparatively lower 5-year survival rate (3). Due to its lack of responsiveness to endocrine therapy and HER2 targeted treatments, therapeutic options for TNBC are significantly limited. In recent years, the success of immune checkpoint inhibitors (ICIs), particularly those targeting programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1), in treating various solid tumors has provided new hope for TNBC immunotherapy and combination chemotherapy strategies (4).

A previous study has shown that TNBC is enriched in tumor-infiltrating lymphocytes (TILs) and has higher immunogenicity than other breast cancer subtypes (5). TNBC is more likely to benefit from immunotherapy than other subtypes. However, the available data are not promising: although the early IMpassion 130 clinical trial showed that the anti-PD-L1 antibody atezolizumab combined with albumin-bound paclitaxel significantly reduced the risk of disease-free progression or death in patients with PD-L1⁺ TNBC, however, the recent IMpassion 131 clinical trial showed that atezolizumab combined with paclitaxel did not benefit TNBC patients (6). It can be seen that the actual benefit of immunotherapy in TNBC patients is very limited, and most patients still have poor prognoses. The differences in the results of different clinical trials also suggest the complexity of the TNBC tumor immune microenvironment, which further affects the therapeutic effect of immune checkpoint inhibitors. Therefore, to achieve the success of immunotherapy, it is necessary to validate other effective immunotherapy targets in TNBC and further study their relationship with tumor microenvironment (TME) and rationally design personalized combination therapies.

CD155, also known as the poliovirus receptor (PVR) or necl-5, is a member of the immunoglobulin superfamily, sharing conserved amino acid sequences and structural homology within this protein class (7). Analogous to the PD-1/PD-L1 axis, CD155 interacts with TIGIT receptors on natural killer (NK) cells and T cells (8). When overexpressed on tumor surfaces, CD155 binding to TIGIT suppresses cytotoxic activity against tumor cells, amplifies immunosuppressive responses mediated by regulatory T cells (Tregs), and collectively dampens T cell functionality, thereby facilitating tumor immune evasion (9). Given its pivotal role in immune regulation, CD155 has emerged as a promising therapeutic target in cancer immunotherapy (10).

TME, a critical determinant of immunotherapy efficacy, also significantly influences the pathogenesis and progression of TNBC (11). Accumulating evidence highlights the TME as a reservoir of novel therapeutic targets for cancer immunotherapy. While the interplay between immune checkpoint molecules and the TME has garnered increasing attention, the specific role of CD155 in TNBC pathogenesis, its association with immune cell infiltration within the TME, and its prognostic implications remain poorly characterized. This study investigates the correlation between CD155 expression and the infiltration of key TME immune cell markers (CD4⁺, CD8⁺, and CD163⁺ cells) in TNBC patients while also evaluating its relationship with clinical outcomes. These findings aim to establish a novel theoretical foundation and inform targeted intervention strategies for advancing TNBC immunotherapy. We present this article in accordance with the REMARK reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-643/rc).

Methods

Patients and tissue specimens

A retrospective cohort of 1,256 breast cancer patients who underwent surgical treatment at The First Affiliated Hospital of Bengbu Medical University between January 2014 and December 2018 was analyzed. From this cohort, 182 TNBC tissue specimens meeting the following criteria were included: (I) complete clinical documentation; (II) unambiguous pathological confirmation; and (III) comprehensive postoperative follow-up data. All breast tissue sections were independently re-evaluated by two senior breast pathologists (Xiaomeng Gong and Qing Zhu) in a blinded manner to verify diagnoses and identify appropriate samples for analysis. Written informed consent was obtained from all participants during their clinical care. This study adhered to the ethical principles of the Declaration of Helsinki and its subsequent amendments, and received approval from the Institutional Ethics Committee of The First Affiliated Hospital of Bengbu Medical University {approval No. [2024]160}.

Bioinformatics of correlation of CD155 with tumor progression and immune cells

Data source and preprocessing

Transcriptomic analysis data with clinical information were downloaded from the The Cancer Genome Atlas-Breast Invasive Carcinoma (TCGA-BRCA) project using R (version 4.0.2) and the R package TCGAbiolinks. A total of 190 TNBC cases were selected. Cases with complete clinical information [age, sex, tumor (T) stage, node (N) stage, metastasis (M) stage, and prognosis] were included. The raw gene expression data for the 190 primary solid tumor samples were preprocessed using log2[fragments per kilobase of transcript per million mapped reads (FPKM)+1] transformation, and differential analysis was performed using HTSeq-Counts.

Genome Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG)

GO and KEGG enrichment analyses were conducted using the R software with the clusterProfiler, enrichment, and ggplot2 packages. Only terms with both P values and q-values less than 0.05 were considered significantly enriched.

Gene set enrichment analysis (GSEA)

To explore the potential functions of CD155, we performed GSEA using the R package clusterProfiler to estimate altered signaling pathways between high and low CD155 expression groups. The C7 immunologic signatures gene set was obtained from msigdb_v7.0_GMTs, which is a collection of genes related to immune system functions.

Xcell

The xCellAnalysis algorithm was used to estimate the infiltration levels of 64 immune cell types in tumor samples. Based on the median expression of CD155 in tumor samples, the cases were divided into high and low CD155 expression groups. The correlation between CD155 expression levels and the infiltration of immune cells was then analyzed.

Assessment of TILs

Patients were stratified into low and high immune infiltration groups based on the median TIL value. TILs were categorized into two groups: intratumoral TILs (iTILs): lymphocytes in direct contact with cancer cells within the tumor. Stromal TILs (sTILs): lymphocytes located in the stroma within the infiltrating boundary, including those within 1 mm of the invasive margin, but not in direct contact with cancer cells. This study primarily focused on sTILs, excluding TILs located distant from the invasive margin of the tumor nests.

Immunohistochemistry (IHC) procedure

Formalin-fixed paraffin-embedded (FFPE) tissue sections were processed using a standardized protocol for each case. Hematoxylin and eosin (H&E)-stained sections (4 µm thickness) were re-evaluated to assess the histological characteristics of the tumors. IHC was performed using the Elivision technique. The following ready-to-use monoclonal antibodies were employed: estrogen receptor (ER) (clone SP1), progesterone receptor (PR) (clone 1SP2), HER2 (clone MXR001), Ki67 (clone MIB-1), CD4 (clone SP35), CD8 (clone SP16), and CD163 (clone MX081), all sourced from Maixin Biotech, Inc. (Fuzhou, China). Additionally, CD155 (clone ab267788) was obtained from Abcam.

ER and PR expression: positive expression was defined as nuclear labeling in ≥1% of tumor cells. HER2 expression: immunoreactivity was scored on a scale of 0–3 based on membrane staining intensity and the proportion of invasive tumor cells, following the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) clinical practice guidelines. A score of 3+ (strong complete membrane staining in >10% of tumor cells) was considered positive. Scores of 0–1+ were classified as negative, while 2+ cases underwent further validation using fluorescence in situ hybridization (FISH). A FISH ratio of ≥2.0 was considered indicative of HER2 gene amplification.

TILs in all samples were immunohistochemically stained for CD8, CD4, and CD163 markers. Positive cells were manually quantified by counting five high-power fields (HPF) within regions of maximal staining intensity. Each slide was initially scanned at low magnification (×100) to identify the “hotspot” area with the highest density of positively stained cells. The mean number of tumor-infiltrating immune cells across these regions was systematically evaluated for each specimen. For statistical comparisons, cases were stratified into lower and higher infiltration groups using median-derived cutoff values.

CD155 immunostaining was predominantly localized to tumor cell membranes. Staining intensity and distribution were scored according to established criteria: intensity scoring: 0: no staining; 1: weak/incomplete membranous staining; 2: weak complete or strong incomplete staining; 3: strong complete membranous staining. Percentage scoring: 0: 0–10% positive tumor cells; 1: 11–25%; 2: 26–50%; 3: ≥50%. The final composite score was calculated by multiplying the intensity score by the percentage score. Total scores were categorized as follows: low expression (0–4) and high expression (5–9).

Statistical analysis

In this study, the median value of immune cell subset counts was utilized as the cutoff for stratifying immune cell populations. Associations between immune cell subsets and clinicopathological parameters were evaluated using Spearman correlation analysis, while categorical relationships involving immune checkpoint molecular markers were assessed via the χ² test. Prognostic factors in TNBC were analyzed through Kaplan-Meier survival curves for univariate evaluation and Cox proportional hazards regression models for multivariate analysis. All statistical tests were two-sided, with a significance threshold set at P<0.05. Data analysis and visualization were performed using GraphPad Prism 9.0 and IBM SPSS Statistics 26.0.

Results

CD155 expression and enrichment analysis in the TCGA-TNBC dataset from the boxplot and paired plot (Figure 1A,1B), CD155 expression is generally higher in the tumor group than in the normal group, with a statistically significant difference (P<0.05). Specifically, CD155 expression levels show a clear upregulation in the tumor group, with significantly higher levels in the tumor samples compared to the normal group. These results suggest that CD155 may play an important role in tumor initiation or progression, and its high expression in tumor tissues may be closely related to the biological characteristics of the tumor.

Figure 1 Bioinformatics of correlation of CD155 with tumor progression and immune cells. (A,B) CD155 expression is generally higher in the tumor group than in the normal group (P<0.05). (C,D) GO and KEGG enrichment analysis results showed that CD155 was closely associated with multiple immune responses and neuro-signaling pathways. (E) GSEA analysis results demonstrate that CD155 plays an important role in immune responses. (F) Xcell results demonstrate the correlation between CD155 expression and the infiltration of various immune cell types. ns, not significant; *, P<0.05; **, P<0.01; ***, P<0.001. GO, Genome Ontology; GSEA, gene set enrichment analysis; KEGG, Kyoto Encyclopedia of Genes and Genomes; PVR, poliovirus receptor.

GO and KEGG enrichment analysis results

From Figure 1C,1D, CD155 is closely associated with multiple immune responses and neuro-signaling pathways, particularly showing significant correlations with neuropeptide signaling, antimicrobial immune response, and humoral immune response. Further KEGG pathway enrichment analysis reveals that CD155 plays an important role in biological processes such as neuro-signaling, immune regulation, metabolism, and cardiomyopathy. These findings suggest that CD155 not only has a potential regulatory role in immune responses but may also play a critical role in neuro-signaling and related diseases.

GSEA results

The GSEA analysis results demonstrate that CD155 plays an important role in immune responses, particularly showing significant enrichment in humoral immune response, vaccine response, and antimicrobial immune response (Figure 1E). Specifically, CD155-related immune pathways involve the activation and immune regulation of T cells, monocytes, and B cells, further suggesting that CD155 may play a key role in immune responses by regulating the function of these immune cells. These findings provide new insights into the potential role of CD155 in the immune system and may offer important clues for the study of related immune diseases.

Xcell results

To further explore the potential role of CD155 in the TME, we employed bioinformatic methods to analyze the relationship between CD155 expression and tumor immune cell infiltration in TNBC (Figure 1F). By integrating TNBC datasets, we evaluated the correlation between CD155 expression and the infiltration of various immune cell types (e.g., T cells, macrophages, B cells). This analysis aims to reveal the role of CD155 in the immune microenvironment and further investigate its potential function in tumor immune evasion and immune regulation.

Clinicopathological features of TNBC patients

Table 1 summarizes the clinicopathological features of 182 TNBC patients included in this study. The mean age of the cohort was 52 years (range, 24–83 years). Histologically, 94.0% (n=171) of cases were classified as invasive carcinoma of no special type (NST), while the remaining 6.0% (n=11) comprised specific subtypes, including three cases of metaplastic carcinoma, six cases of apocrine differentiated carcinoma, and five cases of carcinoma with medullary features.

Regarding surgical management, 121 patients underwent modified radical mastectomy, 32 patients received simple mastectomy with sentinel lymph node biopsy, and 29 patients underwent breast-conserving surgery with radical resection. Postoperatively, adjuvant radiation therapy was administered to 136 patients (74.7%).

Association of CD155 expression and sTILs infiltration with clinicopathological features in TNBC

Among the 182 TNBC patients, 131 (72.0%) exhibited high CD155 expression (Figure 2A), while 51 (28.0%) showed low expression (Figure 2B). Significant differences were observed between CD155 expression with tumor diameter, lymph node metastasis and Ki-67 status (P<0.05). No correlations were identified with patient age and histological grade (P>0.05).

Figure 2 Immunohistochemical results of CD155, immune cell subsets expression and sTILs infiltration in TNBC tissues. (A) High expression of CD155 in TNBC tissues with IHC. (B) Low expression of CD155 in TNBC tissues with IHC. (C) sTILs infiltration in TNBC tissues with HE staining. (D) Positive expression of CD8 in TNBC tissues with IHC (×200). (E) Positive expression of CD4 in TNBC tissues with IHC (×200). (F) Positive expression of CD163 in TNBC tissues with IHC (×200). HE, hematoxylin-eosin; IHC, immunohistochemistry; sTILs, stromal tumor-infiltrating lymphocytes; TNBC, triple-negative breast cancer.

The median stromal tumor-infiltrating lymphocyte (sTILs) infiltration level across the cohort was 30% (Figure 2C). Patients were stratified into low sTILs (n=112, 61.5%) and high sTILs (n=70, 38.5%) groups. sTILs infiltration demonstrated significant negative correlation with lymph node metastasis (r_s=−0.189, P=0.01) and positive correlation with Ki-67 status (r_s=0.390, P<0.001). No associations were observed with age, tumor size, or histological grade (P>0.05) (Table 2).

Association of immune cell infiltration with clinicopathological features and CD155 expression in TNBC

The infiltration levels of three immune cell subsets were quantified as follows: CD8⁺ T cells: median: 70 cells/HPF [range, 0–290 cells/HPF; interquartile range (IQR), 35–120 cells/HPF] (Figure 2D). CD4⁺ T cells: median 76 cells/HPF (range, 0–280 cells/HPF; IQR, 50–127 cells/HPF) (Figure 2E). CD163⁺ M2 macrophages: median: 82 cells/HPF (range, 5–260 cells/HPF; IQR, 30–105 cells/HPF) (Figure 2F). Each immune cell subset was stratified into high and low expression groups based on the median value. Correlation analyses revealed the following associations: CD8⁺ sTILs: negatively correlated with lymph node metastasis (r_s=−0.240, P=0.001) and positively correlated with Ki-67 status (r_s=0.367, P<0.001). CD4⁺ sTILs: negatively correlated with lymph node metastasis (r_s=−0.184, P=0.01). CD163⁺ sTILs: positively correlated with histological grade (r_s=0.164, P=0.03) and Ki-67 status (r_s=0.147, P=0.048) (Table 3). Furthermore, the infiltration levels of CD8⁺ T cells, CD4⁺ T cells, and CD163⁺ M2 macrophages were all significantly correlated with sTILs content. Among these CD8⁺ T cells exhibited the strongest correlation with sTILs (r_s=0.731), followed by CD4⁺ T cells (r_s=0.393) and CD163⁺ M2 macrophages (r_s=0.207). Spearman correlation analysis showed that CD155 expression level was positively correlated with CD163 expression level in TME (P<0.05).

Association of CD155, sTILs, and immune cell subsets with TNBC prognosis

In this study, patients were followed postoperatively for 7–99 months (median: 68 months). During follow-up, 46 patients (25.3%) experienced recurrence or metastasis, and 38 patients (20.9%) succumbed to TNBC-related mortality. Univariate analysis: tumor size, histological grade, lymph node metastasis, sTILs infiltration, and immune cell subsets (CD8⁺, CD4⁺, CD163⁺) as well as CD155 expression demonstrated significant associations with both disease-free survival (DFS) and overall survival (OS) (P<0.05) (Table 4). Multivariate analysis: DFS: independent prognostic factors included tumor size, lymph node metastasis, CD8⁺ T cell infiltration, CD163⁺ macrophage infiltration and CD155 expression (P<0.05) (Table 5). OS: significant predictors were lymph node metastasis , CD8⁺ T cell infiltration, CD163⁺ macrophage infiltration and CD155 expression (P<0.05) (Table 6). Kaplan-Meier curves revealed significant differences in DFS and OS between high and low expression groups of CD8⁺ T cells, CD4⁺ T cells, CD163⁺ macrophages, sTILs, and CD155 (P<0.05) (Figures 3,4).

Figure 3 Patient survival curves. Low CD8, CD4 and high CD163 expression is significantly associated with worse prognosis. (A) DFS between high and low CD8 expression groups. (B) OS comparison between high and low CD8 expression groups. (C) DFS comparison between high and low CD4 expression groups. (D) OS comparison between high and low CD4 expression groups. (E) DFS comparison between high and low CD163 expression groups. (F) OS comparison between high and low CD163 expression groups. DFS, disease-free survival; OS, overall survival.

Figure 4 Low sTILs and high CD155 are associated with worse prognosis. (A) DFS comparison between high and low sTILs expression groups. (B) OS comparison between sTILs high expression and low expression groups. (C) DFS comparison between high and low CD155 groups. (D) OS difference between CD155 high and low groups. DFS, disease-free survival; OS, overall survival; sTILs, stromal tumor-infiltrating lymphocytes.

Discussion

CD155, originally identified as the poliovirus receptor (12), has emerged as a multifunctional protein implicated in cell adhesion, proliferation, and immunomodulation (13,14). Growing evidence positions CD155 as a promising antitumor therapeutic target, particularly due to its dual role in tumorigenesis and immune regulation. Its overexpression correlates with aggressive clinicopathological features and poor prognosis across various malignancies, including colorectal cancer, lung adenocarcinoma, pancreatic cancer, and hepatocellular carcinoma (9,15-17). However, its clinical relevance and mechanistic contributions in TNBC remain poorly characterized.

Our study revealed CD155 overexpression in 72.0% of TNBC cases, demonstrating significant associations with adverse clinicopathological parameters including larger tumor diameter, lymph node metastasis and elevated Ki-67 proliferation index (P<0.05). These results are consistent with Yong et al. (18). Importantly, survival analysis disclosed marked disparities in both DFS and OS between CD155-high and CD155-low cohorts (P<0.05).

Mechanistic insights from other malignancies provide potential explanations for these clinical observations. In colon cancer models, CD155 knockdown via shRNA lentivirus attenuated malignant phenotypes by inhibiting migration/invasion via FAK/Src/MMP-2 axis downregulation (19). Cell cycle arrest is mediated by cyclin-dependent kinase regulators (20), Enhanced apoptosis through elevated Bax/Bcl-2 ratio (21). Furthermore, Lu et al. identified CD155-AKT complex formation in cervical cancer, demonstrating subsequent activation of the AKT/mTOR/NF-κB pathway with concomitant suppression of autophagy and apoptosis (11). These molecular mechanisms may collectively underlie CD155’s association with aggressive TNBC features and poor prognosis. Our bioinformatics analysis further suggests CD155’s involvement in nucleic acid metabolism pathways, potentially contributing to its pro-proliferative effects.

As an immune checkpoint ligand, CD155 exhibits paradoxical immunomodulatory functions through differential receptor engagement: immunosuppressive signaling via TIGIT/CD96 binding (22); inhibits NK/T-cell cytotoxicity (23); enhances Treg-mediated immunosuppression (24); facilitates tumor immune escape (25); immunostimulatory signaling through CD226 interaction (25). Notably, TIGIT expression dynamically regulates immune cell activity: Basally low in resting T-cell subsets (memory CD4⁺, regulatory T, CD8⁺) and NK cells (26); upregulated upon immune cell activation; engages multiple ligands in TME. This intricate receptor interplay creates a complex immunobiological landscape, where CD155 may simultaneously activate and suppress anti-tumor immunity depending on cellular context and receptor expression profiles. Our findings suggest that CD155 may be a key regulator of tumor intrinsic malignancy and immune microenvironment remodeling in TNBC.

With the indepth study of TNBC TME, people have realized that the type and number of infiltrating immune cells in TME are important factors affecting the prognosis and therapeutic effect. The immunomodulatory function of CD155 may depend on the specific tumor type and the corresponding TME. Through the bioinformation analysis of TCGA-TNBC database, we also found that CD155 was related to multiple immune responses and neural signaling pathways, and the expression level of CD155 was closely related to a variety of immune cell infiltration such as macrophages, CD4⁺T cells, CD8⁺T cells, etc. Therefore, we further evaluated the expression of sTILs and macrophages, CD4⁺T cells, and CD8⁺T cells in TNBC tissue samples and their relationship with CD155 expression and the prognostic value. This study found that in TNBC sTILs level was negatively correlated with lymph node metastasis and positively correlated with Ki67 status, and the significance was statistically. To a certain extent, as the defense line of the body’s immune system, sTILs can play a certain role in limiting the invasion and progression of tumors when the immune state is high, and the proliferation state of the tumor itself determines that the body needs to use the corresponding strong immune level to fight against it. Univariate prognostic analysis showed that higher sTILs level was significantly correlated with better DFS and OS, but Cox multivariate regression analysis, which included all relevant factors in this study, failed to conclude that sTILs were an independent prognostic indicator. The reasons for analysis also precisely indicate that sTILs, as a heterogeneous population with multiple cell types, are slightly rough in terms of response and prognosis characteristics. We should further refine the composition of sTILs to find markers that are more closely related to tumor immune status and clinical prognosis. CD8 antibodies are T lymphocyte co-receptors that bind to major histocompatibility complex (MHC)-class I molecules and are mainly distributed in cytotoxic T cells (27). In this study, the number of CD8⁺T lymphocytes was negatively correlated with lymph node metastasis, positively correlated with Ki67 level, and significantly positively correlated with sTILs content (r_s=0.731, P<0.001). This phenomenon verified the clinical significance of CD8⁺T cells consistent with sTILs. CD4⁺T cells can be activated by MHC molecules and differentiated into Th1, Th2, Th17, Tfh, Treg, and other subtypes according to the level of cytokines in TME, and each subtype plays a different function (27). In this group of cases, we studied the overall CD4⁺T cell content in TNBC and its relationship with clinicopathological factors and prognosis and found that the content and distribution of CD4⁺T cells in tissues were consistent with CD8⁺T cells. In terms of clinicopathological factors, CD4⁺T cells were negatively correlated with the number of lymph node metastases. Kaplan-Meier survival curve indicated that there was a significant difference in survival rate between patients with high and low CD4⁺ expression, and univariate prognostic analysis also indicated that CD4⁺T cells were correlated with DFS and OS. However, the value of CD4⁺T cells as an independent prognostic factor was not found in multivariate Cox regression analysis. This supports the potential significance of CD4⁺ T cells as an anti-tumor immune factor for TNBC prognosis. CD163 is considered to be a highly specific marker of M2 macrophages (28). In this study, we found that the number of CD163⁺M2 macrophages was positively correlated with histological grade and Ki67 level, suggesting that CD163⁺M2 macrophages often appeared in malignant TNBC with high histological grade and high proliferation index. Both univariate and multivariate Cox regression analyses indicated that CD163⁺M2 macrophages were an independent risk factor for TNBC prognosis. Previous experiments have also shown that high-density M2 macrophage infiltration is significantly associated with reduced survival of breast cancer patients (29). M2 macrophages can directly stimulate the proliferation of cancer cells or produce related factors to promote angiogenesis and lymphatic angiogenesis, inhibit local immunity, and play an important role in tumor growth, invasion, and metastasis (30). The observation of immune subsets in different regions of TNBC tumors also inspired us to further think that the distribution of immune populations in TME is a dynamic process of pro-tumor or anti-tumor effects, and favorable immune characteristics slow down the growth of tumors. There has been evidence that some chemokines can selectively attract CD8⁺T cells in different tumor regions, and adaptive immunity still plays a role in delaying tumor progression during the progression of TNBC (immune escape phase) (31). Changes in immune cell density and function that occur during disease progression may support tumors to evade immune surveillance. The beneficial effects of anti-tumor immunity may persist during tumor progression, potentially diminishing tumor invasion potential and leading to better clinical outcomes. Therefore, the state of immune infiltration in tumors not only reflects the preexisting immunity of the body but also reflects the immune state during treatment. Capturing this information will influence patient management decisions.

Our findings reveal a significant positive correlation between CD155 expression and CD163⁺ M2 macrophage infiltration (r_s=0.380, P=0.016), suggesting that CD155 may orchestrate M2 polarization to establish an immunosuppressive TME. This aligns with Huang et al.’s mechanistic study in cisplatin-resistant lung cancer, where CD155-Src axis activation drove tumor-associated macrophage (TAM) polarization toward M2 phenotype through macrophage migration inhibitory factor (MIF) upregulation, ultimately accelerating tumor progression (32). We also observed that CD155 overexpression was associated with poor DFS and OS in TNBC, potentially through its interaction with immune cells such as CD163⁺ macrophages. This is consistent with the findings of Huang (32) and Boissière-Michot (26). In the prognostic analysis, we also performed stratified analyses of patients. For example, stratification based on clinical stage (TNM) revealed that pT3 and pN2/N3 were significantly associated with worse DFS and OS, and were identified as independent prognostic factors. Stratification based on the degree of immune cell infiltration (sTILs, CD8, CD4, CD163) showed that CD8, CD4, CD163 subsets were all associated with survival, and in multivariate analysis, CD8 and CD163 were independent prognostic factors for both DFS and OS. At present, there are few studies on the relationship between CD155 and CD163 in malignant tumors, especially the role of TNBC. Further exploration of the interaction between CD155 and macrophages is needed to discover more effective therapeutic strategies for blocking tumor immunosuppression. Boissière-Michot et al. observed significant correlation among CD155 expression and high TILs infiltration, CD8 T cells which differs from our results (26). These discrepancies may relate to the sample sizes selected in different experiments and at the same time reflect the heterogeneity of the immune landscape among TNBC subtypes.

Due to the limitations of our current experimental approaches, we only evaluated the association between CD155 expression and immune cell infiltration by IHC. Stamm et al. reported that, in vitro, blocking TIGIT or PVR enhanced immune cell-mediated lysis of breast cancer cell lines including SKBR-3, MDA-MB-231, MDA-MB-468, and BT-549, suggesting that inhibition of the TIGIT-PVR axis may represent a novel therapeutic strategy for breast cancer (33). Similarly, Chen et al. (34) demonstrated that P/PEAL-siCD155 nanoparticles exhibited excellent TNBC-targeting properties and induced CD8⁺ TIL-dominant antitumor immunity, thereby efficiently suppressing TNBC progression and metastasis with favorable safety in a syngeneic 4T1 orthotopic TNBC model. Collectively, these studies support CD155 as an emerging and promising immunotherapeutic target with significant potential for clinical translation. In future experiments, we will further verify through in vitro studies whether anti-CD155 antibodies can enhance the sensitivity of TNBC cells to immune cells, as well as their interaction with PD-1 inhibitors. In summary, CD155 plays an important role in the evolution of TNBC. High expression of CD155 in TNBC is associated with poor prognosis. CD155 may promote tumor progression by promoting TNBC tumor proliferation and metastasis, inducing immunosuppression, and affecting the infiltration level and function of immune cells in TME. Moreover, CD155 expression and the level of immune cell infiltration in TME can jointly predict the prognosis of TNBC patients. These findings suggest that CD155 may be a valuable target for TNBC immunotherapy.

Conclusions

High expression of CD155 in TNBC is associated with aggressive clinicopathological features (tumor diameter, lymph node metastasis, and Ki-67 proliferation index) and poor prognosis. Overexpression of CD155 may contribute to the formation of the immunosuppressive TME mediated by M2 macrophages. CD155 overexpression introduced a worse relapse-free and OS and might be a potential immunotherapy target in TNBC patients. Based on these findings, we conclude that CD155 plays an important role in the development of TNBC and is expected to become a novel target for TNBC immunotherapy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-643/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-643/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-643/prf

Funding: This study was supported by Key Projects of the Department of Education of Anhui Province (Nos. 2023AH051980, 2022AH051479, KJ2021A0769 and KJ2020A0593), Overseas Visiting Scholar and Training Program for Young Key Teachers of Anhui Provincial Department of Education (No. JWFX2024020), Clinical Research Special Fund of WU JIEPING Medical Foundation (No. 320.6750.2022-19-79), Open Project of Anhui Province Key Laboratory of Cancer Translational Medicine (No. KFDX202203), and Anhui Provincial Education Department 2024 Annual Graduate Research Innovation Plan at Bengbu Medical University (No. byycxz24009).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-643/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics Committee of The First Affiliated Hospital of Bengbu Medical University {approval No. [2024]160}. Written informed consent was obtained from all participants during their clinical care.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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