Abstract Metastatic melanoma remains a significant clinical challenge despite recent advances with immune checkpoint inhibitors (ICIs) like anti-programmed cell death-1 (PD-1), which show variable efficacy across metastatic organ sites. The lung is a frequent site of metastasis, and while complete responses to ICIs occur more often in pulmonary lesions than in other organs, up to 60% of patients with lung metastases fail to respond. Pulmonary metastases are also a leading cause of death in patients with metastatic melanoma. This suggests that we will need to comprehensively understand the tumor immune microenvironments of pulmonary metastatic melanoma including the expression of alternative immune checkpoint targets. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an emerging checkpoint molecule predominantly expressed in myeloid cells that suppresses immune activation. We found that VISTA was highly expressed in human pulmonary metastatic melanoma while PD-L1 expression was not significantly elevated. To investigate the role of VISTA in pulmonary metastatic melanoma, we utilized a variety of mouse models with B16-F10 murine melanoma. VISTA knock-out (KO) mice develop significantly fewer lung metastases than wild-type (WT) controls (lung-to-body weight ratio: VISTA WT = 0.05 ± 0.018, VISTA KO = 0.02 ± 0.011; p = 0.0012), with no difference in subcutaneous tumor growth (p = 0.1625). We assessed the immune cell infiltration in these mice. VISTA KO mice had significantly more proinflammatory monocytes (2.78% ± 1.50 vs. 0.52% ± 0.54; p = 0.0003) and macrophages (14.27% ± 6.18 vs. 6.75% ± 4.27; p = 0.006) in the metastatic lung tissue compared to WT mice. These data suggest that myeloid cell VISTA promotes lung metastasis of melanoma. We also demonstrated that Rag1-/- mice, which lack T and B lymphocytes, showed increased melanoma lung metastases compared to Rag1-/- VISTA-/- mice, suggesting that the metastatic phenotype is independent of T and B lymphocytes (Rag1-/- = 0.03 ± 0.008, Rag1-/- VISTA-/- = 0.01 ± 0.002; p = 0.0008). Mechanistically, VISTA-deficient bone marrow-derived macrophages (BMDMs) produce more TNFα and nitric oxide compared to WT BMDMs, indicating that VISTA suppresses macrophage activation as a mechanism of immune suppression (TNFα: 1.2-fold-change, 1166 vs. 946.3 pg/ml; p = 0.0001; nitric oxide: 3.2-fold-change, 29.42 vs. 9.089 µmol/L). Our findings establish VISTA as a critical regulator of immune suppression in pulmonary melanoma metastases. Ongoing mechanistic studies will clarify its potential as a therapeutic target, leading to improved treatment strategies and patient outcomes. Citation Format: Carly M. Fielder, Qianni Hu, Hyundong Yoon, Raymond Zhang, Anjali Raman, Megan L. Tigue, Chi Yan, Vivian L. Weiss, Douglas B. Johnson, Jin Chen, Tae Kon Kim. The role of VISTA in the lung tumor microenvironment of metastatic melanoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6556.
Fielder et al. (Fri,) studied this question.