Breast cancer (BRCA) is a prevalent malignancy in female and with the tendency to occur in younger women worldwide.1 Despite the major progress was received in early screening and later treatment strategies for BRCA, the patients who under remission still meet the challenges of tumor relapse or metastasis events.2 Based on the different molecular signatures, such as human epidermal growth factor receptor‐2 (HER2), progesterone receptors (PR) and estrogen receptors (ER), four subtypes of BRCA could be divided, including basal‐like (ER-, PR-, and HER2-), HER2(ER-, PR-, and HER2+), luminal A (ER+and/or PR+, and HER2-), and luminal B (ER+ and/or PR +, HER2+).3 Recently, HER2 targeted (like Trastuzumab) and hormone therapy (such as Everolimus and Anastrozole) have dramatically improved the survival rates of patients with HER2 positive and hormone receptor positive, respectively.4 While triple‐negative breast cancer (TNBC), as the dominant type of basal‐like subtype and unlike other subtypes of BRCA, has no specific therapeutic strategy due to the high heterogeneity and early metastasis. Even with the standard chemotherapy regimens, only 20% of patients with TNBC benefit. Therefore, patients with TNBC always have a predisposition to the worst prognosis.
To reveal the heterogeneity of TNBC, some studies had described the expression profile–based characteristics and successfully divided TNBC into four subtypes from genomic and transcriptomic landscape, including mesenchymal‐like, basal‐like immune‐suppressed, immunomodulatory, and luminal androgen receptor (LAR). Except the LAR, the mechanisms of the other three subtypes were all involved in the immune‐related pathways, suggesting that the high immunogenicity in TNBC initiation.5 Meanwhile, other researchers had classified TNBC expression profiles into three microenvironment clusters with distinct potential immune escape mechanisms using multiomics data.6 These evidence suggested that immune escape mechanisms might be the determinant factor for TNBC heterogeneity. Furthermore, The molecule‐based immunotherapy has been achieved in some malignant cancers, like melanoma or non–small cell lung cancer, by targeting programmed death ligand‐1, programmed death‐1, and cytotoxic T lymphocyte–associated antigen 4 (CTLA4).7,8 Therefore, to elucidate the underlying immune escape mechanisms and screen the actionable targets for immunotherapy might be greatly significant to achieve the precise treatment for TNBC.
Butyrophilin subfamily 3 (BTN3A, CD277), as a B7 family member, composes the homolog at the cytomembrane and acts as the immunoglobulins receptors or biomarkers for various immune cells.9Studies had suggested that BTN3A exerts as a crucial role in helping Vγ9Vδ2 T cells recognize tumor cells through T‐cell receptor mediated sensing of phosphoAntigens,10 and agonists (or antagonist) of BTN3A could enhance (or abrogate) Vγ9Vδ2 T cell–mediated lysis of tumor cells.11,12 BTN3A2, as well as BTN3A1 and BTN3A3, belongs to the BTN3A subfamily and is the component of BTN3A. It was suggested that the higher BTN3A2 expression in OV, whether at the messenger RNA (mRNA) or protein level, had an association with T‐cell infiltration and a better prognosis.13 Nevertheless, the underlying role of BTN3A2 in regulating the immune infiltration and prognosis of TNBC are still unclear.
In this study, BTN3A2 was identified as a special diagnostic and independently prognostic marker for TNBC and was highly correlated with immune cells infiltration. Besides, BTN3A2 was positively correlated with general T cells, CD8+ T cells, Th1 cells, dendritic cells (DCs) infiltrations, and T cells exhaustion in TNBC. T‐cell receptor interaction and nuclear factor‐κB (NF‐κB) signaling pathways might be the involved mechanisms of BTN3A2 regulating the immune infiltration. The study shed light on the relationship of BTN3A2 with diagnose and prognosis of TNBC and uncovered the mechanism of BTN3A2 in TNBC immunology.
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