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The Expression Pattern and Clinical Significance of the Immune Checkpoint Regulator VISTA in Human Breast Cancer
Xiaoxue Xie1, Junying Zhang2, Zhongyuan Shi3
1Jiangsu Key Lab of Drug Screening, China Pharmaceutical University, Nanjing, China.
Background:
Immunotherapies targeting CTLA-4 and PD-1 have elicited promising responses in a variety of cancers. However, the relatively low response rates warrant the identification of additional immunosuppressive pathways. V domain immunoglobulin suppressor of T cell activation (VISTA) plays a critical role in antitumor immunity and is a valuable target in cancer immunotherapy.
Methods:
Here, we used single-cell RNA-seq to analyze the gene expression levels of 14897 cells from a breast cancer sample and its paired 7,320 normal cells. Then, we validated the protein expression of immune checkpoint molecules (VISTA, PD-1, PD-L1, TIGIT, TIM3, and LAG3) in 324 human breast cancer samples by immunohistochemistry and quantitative immunofluorescence (QIF) approaches.
Results:
Single cell RNA-seq results show a higher level of immune checkpoint VISTA expression in breast cancer tissue compared to adjacent normal tissue. We also found that VISTA expressed highest in breast cancer tissue than other immune-checkpoints. Immunohistochemical results showed that VISTA was detected with a membranous/cytoplasmic staining pattern in intratumoral immune cells and breast cancer cells. Additionally, VISTA was positively correlated with pathological grade, lymph node status and the levels of PD-1 according to the chi-square test or Fisher's test. Furthermore, VISTA expression was higher in CD68+ tumor-associated macrophages (TAMs) than in CD4+ T cells, CD8+ cytotoxic T cells or CD20+ B cells.
Conclusions:
These findings therefore support the immunoregulatory role of VISTA in breast cancer and indicate that targeting VISTA may benefit breast cancer immunotherapy.
Insights
V domain immunoglobulin suppressor of T cell activation (VISTA) is highly expressed in breast cancer, particularly in tumor-associated macrophages. Targeting VISTA may improve immunotherapy responses in breast cancer patients.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune checkpoint inhibitors targeting CTLA-4 and PD-1 show promise but have limited response rates.
- Identifying novel immunosuppressive pathways is crucial for advancing cancer immunotherapy.
- V domain immunoglobulin suppressor of T cell activation (VISTA) is recognized for its critical role in antitumor immunity.
Purpose of the Study:
- To investigate the expression and role of VISTA in breast cancer.
- To compare VISTA expression with other immune checkpoints in breast cancer.
- To explore the potential of VISTA as a therapeutic target in breast cancer immunotherapy.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was used to analyze gene expression in breast cancer and normal tissues.
- Protein expression of immune checkpoint molecules, including VISTA, was validated using immunohistochemistry and quantitative immunofluorescence (QIF) in human breast cancer samples.
- Statistical analyses, including chi-square and Fisher's tests, were employed to correlate VISTA expression with clinical parameters.
Main Results:
- scRNA-seq revealed significantly higher VISTA expression in breast cancer tissue compared to adjacent normal tissue.
- VISTA exhibited the highest expression among the investigated immune checkpoints in breast cancer.
- VISTA protein was detected in both intratumoral immune cells and breast cancer cells, with higher expression in tumor-associated macrophages (TAMs) compared to T cells and B cells.
- VISTA expression positively correlated with higher pathological grade and lymph node status.
Conclusions:
- VISTA plays a significant immunoregulatory role in the breast cancer microenvironment.
- The findings support VISTA as a potential therapeutic target to enhance the efficacy of breast cancer immunotherapy.
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