Exploring IgSF11 as a potential immune checkpoint and immunotherapeutic target in breast cancer

The immunoglobulin superfamily 11 (IgSF11) represents a novel immune checkpoint ligand, increasingly recognized as a promising candidate for cancer immunotherapy. In this study, we investigated the clinicopathological significance of IgSF11 expression and its correlation with inhibitory immune checkpoints, including programmed cell death 1 (PD-1), its ligand PD-L1, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), as well as V-domain Ig suppressor of T cell activation (VISTA), within the tumor microenvironment of breast cancer patients. Two complementary approaches were employed, encompassing transcriptomic analysis using large-scale datasets, namely the Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts, as well as a proteomic analysis conducted via immunohistochemistry (IHC) in a Moroccan cohort. Our transcriptomic findings suggest that IgSF11 mRNA expression is associated with aggressive clinicopathological features, particularly the basal-like breast cancer molecular subtype, and shows a positive correlation with inhibitory immune checkpoints, most notably its receptor VISTA. Additionally, gene set enrichment analysis (GSEA) demonstrated a significant association between a high IgSF11 expression and key tumor-promoting pathways, including epithelial-mesenchymal transition, angiogenesis, hypoxia, and immunosuppression. IHC analysis further revealed that IgSF11 staining was significantly upregulated in breast tumor tissues compared to adjacent uninvaded control tissues. Unexpectedly, IgSF11 protein was uniformly positive across all breast cancer molecular subtypes, and exhibited a trend toward a negative correlation with VISTA. Taken together, our data suggest that IgSF11 expression may play a central role in breast cancer pathogenesis and immune evasion supporting the potential of IgSF11 blockade as a promising immunotherapeutic strategy for breast cancer patients.