Journal
CELL REPORTS
Volume 30, Issue 2, Pages 510-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.12.036
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Funding
- National Institutes of Health (NIH) [R01 CA196278, R01 CA160495, R01 AR043369-22, R01 CA222871-02, R01 AR072304-02, 5P01 CA163222-05, 1F99CA245552-01, T32 GM 100836-5]
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation awards
- NIH/National Cancer Institute Support Grant [P30 CA056036]
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Immune checkpoint inhibitors have improved patient survival in melanoma, but the innate resistance of many patients necessitates the investigation of alternative immune targets. Many immune checkpoint proteins lack proper characterization, including V-domain Ig suppressor of T cell activation (VISTA). VISTA expression on immune cells can suppress T cell activity; however, few studies have investigated its expression and regulation in cancer cells. In this study, we observe that VISTA is expressed in melanoma patient samples and cell lines. Tumor cell-specific expression of VISTA promotes tumor onset in vivo, associated with increased intratumoral T regulatory cells, and enhanced PDL-1 expression on tumor-infiltrating macrophages. VISTA transcript levels are regulated by the stemness factor Forkhead box D3 (FOXD3). BRAF inhibition upregulates FOXD3 and reduces VISTA expression. Overall, this study demonstrates melanoma cell expression of VISTA and its regulation by FOXD3, contributing to the rationale for therapeutic strategies that combine targeted inhibitors with immune checkpoint blockade.
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