In a groundbreaking study that could redefine the landscape of breast cancer treatment, researchers have unveiled critical insights into the expression patterns and clinical significance of several immune checkpoint molecules – CD155, FGL1, Galectin-9, and PD-L1 – in breast cancer patients undergoing neoadjuvant chemotherapy. This comprehensive investigation published in Medical Oncology not only deepens our understanding of tumor immune evasion but also opens new avenues for precision immunotherapy in one of the most common and life-threatening malignancies affecting women worldwide.
Breast cancer remains a formidable challenge in oncology, with neoadjuvant chemotherapy serving as a cornerstone treatment strategy aimed at reducing tumor size before surgery. However, therapeutic resistance and tumor recurrence frequently undermine long-term patient outcomes. The tumor microenvironment, particularly the dynamic interplay between cancer cells and the immune system, has been implicated in dictating the response to chemotherapy. Immune checkpoint molecules such as PD-L1 have already been established as vital regulators of immune tolerance within tumors, but less is known about the co-expression and interplay of other counterparts such as CD155, FGL1, and Galectin-9.
The study meticulously quantified the expression levels of these molecules in tumor tissues derived from breast cancer patients treated with neoadjuvant chemotherapy. The research team used advanced immunohistochemical techniques, alongside quantitative molecular assays, to delineate the spatial distribution and intensity of marker expression within the tumor microenvironment. Their data revealed a notable upregulation of CD155, FGL1, and Galectin-9 in conjunction with PD-L1, suggesting a multifaceted mechanism by which breast cancer cells might subvert immune surveillance.
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CD155, also known as the poliovirus receptor, is emerging as a significant immune checkpoint ligand that interacts with receptors such as TIGIT and CD96 on T cells and natural killer (NK) cells. By engaging these inhibitory receptors, CD155 facilitates the attenuation of anti-tumor immune responses, allowing cancer cells to evade immune-mediated destruction. Elevated expression of CD155 within breast tumors subjected to neoadjuvant chemotherapy underscores its potential role in therapeutic resistance and immune escape, positioning it as a promising immunotherapeutic target.
Fibrinogen-like protein 1 (FGL1) has recently been identified as a major ligand for the immune checkpoint receptor LAG-3, which, similarly to PD-1/PD-L1 pathways, acts as a brake on T cell activation. The study’s findings demonstrated a significant correlation between FGL1 expression and poor pathological response to chemotherapy, implying that FGL1-mediated immunosuppression may contribute to the failure of neoadjuvant treatment in certain breast cancer subsets. This positions FGL1 as another crucial checkpoint with translational implications for combination immunotherapy.
Galectin-9, a member of the β-galactoside binding protein family, plays diverse roles not only in cell adhesion and apoptosis but also as an immune checkpoint molecule through its interaction with Tim-3 on T cells. By promoting T cell exhaustion and dysfunction, elevated Galectin-9 expression could hamper effective anti-cancer immunity. The researchers showed that increased Galectin-9 levels were associated with aggressive tumor phenotypes and diminished chemotherapy efficacy, further enriching our comprehension of the complex immunoregulatory milieu within breast tumors.
PD-L1, already the poster child of immune checkpoint blockade therapies, was confirmed to be differentially expressed following neoadjuvant chemotherapy. Importantly, the co-expression patterns observed in this study suggest that the interplay between PD-L1 and other novel checkpoint ligands like CD155, FGL1, and Galectin-9 potentially synergizes to create a robust immunosuppressive niche. Such molecular crosstalk presents a sophisticated challenge but also an opportunity for combinational targeting strategies aiming to reinvigorate antitumor immunity.
The clinical implications of these findings are profound. By defining the expression profiles of multiple immune checkpoint molecules in the context of chemotherapy, the study illuminates new biomarkers predictive of treatment response and prognosis. This knowledge empowers clinicians to tailor immunomodulatory treatments based on the specific immunobiological landscape of each tumor, thereby advancing the paradigm of personalized medicine in breast cancer care.
Furthermore, these insights rekindle enthusiasm for the development of multifaceted immune checkpoint inhibitors that simultaneously disrupt several immunosuppressive pathways. For example, dual blockade of PD-L1 and CD155 or FGL1 could overcome resistance mechanisms that monotherapies fail to surmount. Preclinical models inspired by these findings could accelerate the validation of such approaches and their eventual translation into clinical trials.
Technically, the study stands out by integrating a robust methodological framework, combining quantitative immunohistochemistry with RNA expression analysis, allowing for meticulous characterization of immune checkpoint molecule distribution at both the protein and transcript levels. This comprehensive approach facilitates a more nuanced understanding of the temporal and spatial dynamics of these markers during chemotherapy, a critical consideration in designing optimal treatment schedules.
Moreover, the research highlights the heterogeneity of breast cancer subtypes, underscoring that the immunological interplay varies among hormone receptor-positive, HER2-enriched, and triple-negative breast cancers. This heterogeneity demands tailored investigational and therapeutic strategies, as immune checkpoint expression and the consequent tumor-immune interactions might differ drastically depending on molecular subtype.
The timing of immune checkpoint expression changes relative to chemotherapy is another intriguing aspect revealed by the study. Chemotherapy-induced tissue remodeling and stress could modulate the tumor microenvironment, either augmenting or diminishing immune evasion pathways. Understanding these dynamics could optimize the sequence and combination of chemotherapy and immunotherapy to maximize therapeutic efficacy.
Additionally, the intriguing correlation between high expression levels of these immune checkpoint molecules and worse clinical outcomes calls for urgent efforts to incorporate immune profiling into routine diagnostic workflows. Such integration can lead to the stratification of patients most likely to benefit from adjunct immunotherapy, thereby improving survival rates and quality of life.
While this study focuses on breast cancer, the broader implications extend to other solid tumors where neoadjuvant chemotherapy remains a primary treatment modality. The convergence of findings related to CD155, FGL1, Galectin-9, and PD-L1 across different cancers enhances the potential for pan-cancer immunotherapeutic strategies targeting these checkpoints.
In summary, this pioneering research sheds light on the complex immunoregulatory network within breast tumors exposed to neoadjuvant chemotherapy, identifying novel immune checkpoints that could become therapeutic linchpins. The intricate interplay between CD155, FGL1, Galectin-9, and PD-L1 not only challenges existing paradigms but also propels the field toward a future where combination immunotherapies tailored to individual tumor immunophenotypes become standard of care.
As immuno-oncology continues to evolve, studies like this act as harbingers of a new era in cancer treatment, one that transcends conventional chemotherapeutics and embraces the intricacies of immune modulation. A deeper comprehension of these molecular interactions is imperative to unleash the full potential of immunotherapy and improve the arduous journey of breast cancer patients globally.
The translational potential of targeting these immune checkpoints is enormous. Ongoing trials inspired by such foundational research can be anticipated to explore novel inhibitors or antibodies against CD155, FGL1, and Galectin-9, either alone or in concert with PD-L1 inhibitors. The simultaneous blockade of multiple suppressive axes may yield durable responses, reduced relapse, and long-term remissions.
Ultimately, the battle against breast cancer is becoming increasingly sophisticated, guided by insights into the tumor microenvironment’s immunological fabric. As new checkpoints like CD155, FGL1, and Galectin-9 emerge from obscurity into the spotlight, the future of breast cancer therapy looks increasingly hopeful, offering patients renewed promise for survival and wellness.
Subject of Research: Immune checkpoint molecule expression and clinical significance in breast cancer patients undergoing neoadjuvant chemotherapy.
Article Title: Expression and clinical significance of CD155, FGL1, Galectin-9, and PD‑L1 in breast cancer with neoadjuvant chemotherapy.
Article References:
Zeng, Y., Zhao, B., Yan, M. et al. Expression and clinical significance of CD155, FGL1, Galectin-9, and PD‑L1 in breast cancer with neoadjuvant chemotherapy. Med Oncol 42, 375 (2025). https://doi.org/10.1007/s12032-025-02914-y
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Tags: CD155 and breast cancer treatmentchemotherapy response in breast cancerclinical implications of immune evasion in cancerFGL1 expression in tumorsGalectin-9 role in cancer immunologyimmune checkpoint molecules in oncologyimmune markers in breast cancerneoadjuvant chemotherapy and tumor size reductionPD-L1 significance in neoadjuvant therapyprecision immunotherapy for breast cancertumor microenvironment and immune interactiontumor recurrence and therapeutic resistance