@article{423dbd25f1c94906a875ca6c3efe8a73,
title = "FOXD3 Regulates VISTA Expression in Melanoma",
abstract = "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.",
keywords = "DD1α, Dies1, FOXD3, PD-1H, VISTA, VSIR, immune checkpoint",
author = "Rosenbaum, {Sheera R.} and Meghan Knecht and Mehri Mollaee and Zhijiu Zhong and Erkes, {Dan A.} and McCue, {Peter A.} and Inna Chervoneva and Berger, {Adam C.} and Lo, {Jennifer A.} and Fisher, {David E.} and Gershenwald, {Jeffrey E.} and Davies, {Michael A.} and Purwin, {Timothy J.} and Aplin, {Andrew E.}",
note = "Funding Information: This work is supported by grants from National Institutes of Health (NIH) R01 CA196278 and R01 CA160495 to A.E.A.; R01 AR043369-22, R01 CA222871-02, R01 AR072304-02, and 5P01 CA163222-05 to D.E.F.; and in part by 1F99CA245552-01 and T32 GM 100836-5 to S.R.R. In addition, the study was supported by Dr. Miriam and Sheldon G. Adelson Medical Research Foundation awards to A.E.A. M.A.D. and D.E.F. The Sidney Kimmel Cancer Center Flow Cytometry, Translational Pathology, and Meta-Omics core facilities are supported by NIH/National Cancer Institute Support Grant P30 CA056036. We are grateful to Dr. Meenhard Herlyn (Wistar Institute), Dr. Marcus Bosenberg (Yale School of Medicine), and Dr. Constance E. Brinckerhoff and Dr. David Mullins (both at Geisel School of Medicine at Dartmouth) for generously providing cell lines; Christina Nickerson and Christine Sheehan at the Albany Medical Research Histology Core for histology staining; and Conroy Field for optimizing conditions in the animal studies. S.R.R. and A.E.A conceived the study, designed the experiments, analyzed the data, and wrote the manuscript. D.A.E. contributed to the design and analysis of the immunological studies. M.M. Z.Z. and P.A.M. performed the immunohistochemical analyses of tumor tissues contributed by A.C.B. J.E.G. and M.A.D. The tumor microarray data were subsequently analyzed by M.K. under the supervision of T.J.P. TCGA analyses were performed by T.J.P. and critically reviewed by J.E.G. and M.A.D. The D4M UV2 cell line was created and contributed by J.A.L. and D.E.F. The biostatistical analyses of tumor growth delay and tumor volume doubling times were performed by I.C. All of the other experiments were performed by S.R.R. A.E.A. reports receiving a commercial research grant from Pfizer Inc. (2013?2017), has ownership interest in patent number 9880150, and has consulted for SpringWorks Therapeutics and Fortress Biotech within the last 3 years. D.E.F. has a financial interest in Soltego Inc. a company developing SIK inhibitors for topical skin darkening treatments that may be used for a broad set of human applications. D.E.F.?s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. The other authors declare no competing interests. Funding Information: This work is supported by grants from National Institutes of Health (NIH) R01 CA196278 and R01 CA160495 to A.E.A.; R01 AR043369-22 , R01 CA222871-02 , R01 AR072304-02 , and 5P01 CA163222-05 to D.E.F.; and in part by 1F99CA245552-01 and T32 GM 100836-5 to S.R.R. In addition, the study was supported by Dr. Miriam and Sheldon G. Adelson Medical Research Foundation awards to A.E.A., M.A.D., and D.E.F. The Sidney Kimmel Cancer Center Flow Cytometry, Translational Pathology, and Meta-Omics core facilities are supported by NIH/National Cancer Institute Support Grant P30 CA056036 . We are grateful to Dr. Meenhard Herlyn (Wistar Institute), Dr. Marcus Bosenberg (Yale School of Medicine), and Dr. Constance E. Brinckerhoff and Dr. David Mullins (both at Geisel School of Medicine at Dartmouth) for generously providing cell lines; Christina Nickerson and Christine Sheehan at the Albany Medical Research Histology Core for histology staining; and Conroy Field for optimizing conditions in the animal studies. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2020",
month = jan,
day = "14",
doi = "10.1016/j.celrep.2019.12.036",
language = "English (US)",
volume = "30",
pages = "510--524.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}