High VISTA expression is linked to a potent epithelial-mesenchymal transition and is positively correlated with PD1 in breast cancer

Abstract

Breast cancer is the most common type of tumor in women worldwide. Immune checkpoint inhibitors, particularly anti-PDL1, have shown promise as a therapeutic approach for managing this disease. However, this type of immunotherapy still fails to work for some patients, leading researchers to explore alternative immune checkpoint targets. The Ig suppressor of T cell activation domain V (VISTA) has emerged as a novel immune checkpoint that delivers inhibitory signals to T cells and has demonstrated encouraging results in various cancers. Our study investigated the association of VISTA expression with clinicopathological parameters in breast cancer patients, its involvement in the Epithelial-Mesenchymal-Transition (EMT) process, and its correlation with PD1 expression. Transcriptomic analysis revealed that VISTA was associated with lobular and metaplastic histological type, tumor size, lymph node status, ER and PR negative status, and the TNBC molecular subtype. Furthermore, VISTA expression was strongly associated with an immunosuppressive tumor microenvironment. Immunohistochemistry analysis corroborated the transcriptomic results, indicating that VISTA was expressed in most immune cells (94%) and was significantly expressed in breast cancer tumor cells compared to matched adjacent tissues. Our study also showed for the first time that VISTA overexpression in breast cancer cells could be associated with the EMT process. Additionally, we identified a positive correlation between VISTA and PD-1 expression. Together, these results highlight the immunosuppressive effect of VISTA in breast cancer patients and suggest that bi-specific targeting of VISTA and PD-1 in combination therapy could be beneficial for these patients.

On the same side: The immune regulatory protein Vista and its ligands interact in cis

“…Figure 4 shows the co-expression patterns of VISTA with either VSIG8, VSIG3, PSGL-1, or PD-L1 as a positive control. A small correlation between VISTA and PD-L1 mRNA expression was observed, consistent with their known overexpression in multiple cancer types (He et al, 2021;Rezouki et al, 2023). A strong correlation was found between VISTA and PSGL-1 across various cancer types (Figure 4D and SI Figure 3), suggesting a functional connection and supporting a cis interaction-dependent relationship between VISTA and PSGL-1.…”

Identification of New Chemoresistance-Associated Genes in Triple-Negative Breast Cancer by Single-Cell Transcriptomic Analysis

“…These data are presented in Figure 5 and the top 100 differentially expressed genes are listed in Tables S5 and S6. The results of this analysis confirmed that the paclitaxel-resistant cells in cluster 1 (depicted in orange in Figure 5a) resided in a highly mesenchymal state, since, besides the mesenchymal signature described above (Section 2.1), they also overexpressed genes known to induce EMT, including S100A4 [34,35], C10orf54 [36], and WISP1 [37] (Figure 5b). Therefore, it is reasonable to assume that the EMT pathway is involved in the resistance phenotype of these cells and its targeting [38] may be a viable option to restore drug sensitivity.…”

The VISTA/VSIG3/PSGL-1 axis: crosstalk between immune effector cells and cancer cells in invasive ductal breast carcinoma

“…VISTA is an immunological checkpoint protein, and its overexpression, together with increased levels of the VSIG3 and PSGL-1 receptors in the tumor microenvironment, may be involved in the modulation of immune responses to cancer. There is growing evidence of the importance of the immunosuppressive role of VISTA in cancer progression [ 20 , 41 , 57 , 62 , 63 , 69 – 73 ]. The presence of VISTA on the surface of cancer cells can not only modulate immune cells but also potentially play a much broader role in cancer biology.…”