Muñoz Perez, NataliaPensabene, Juliana M.Galbo, Phillip M., Jr.Sadeghipour, NegarXiu, JoanneMoziak, KirstenYazejian, Rita M.Welch, Rachel L.Bell, W. RobertSengupta, SomaAulakh, SonikpreetEberhart, Charles G.Loeb, David M.Eskandar, EmadZheng, DeyouZang, XingxingMartin, Allison M.2024-10-102024-10-102024-07-24Muñoz Perez N, Pensabene JM, Galbo PM Jr, et al. VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma. Cancers (Basel). 2024;16(15):2629. Published 2024 Jul 24. doi:10.3390/cancers16152629https://hdl.handle.net/1805/43866Background: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. Methods: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. Results: Flow cytometry reveals a notable presence of CD45hi/CD11bhi macrophage-like and CD45int/CD11bint microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (Tregs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45hi/CD11bhi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor-cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA's binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. Conclusions: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA-VSIG axis to enhance anti-tumor responses.en-USAttribution 4.0 InternationalMedulloblastomaImmunotherapyImmune checkpoint inhibitorTumor microenvironmentImmune evasionTumor-associated macrophagesT-regulatory cellsV-domain suppressor of T-cell activationArticle