VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma

• Published in: Cancers 2024-08, Vol.16 (15), p.2629
• Main Authors: Muñoz Perez, Natalia, Pensabene, Juliana M, Galbo, Jr, Phillip M, Sadeghipour, Negar, Xiu, Joanne, Moziak, Kirsten, Yazejian, Rita M, Welch, Rachel L, Bell, W Robert, Sengupta, Soma, Aulakh, Sonikpreet, Eberhart, Charles G, Loeb, David M, Eskandar, Emad, Zheng, Deyou, Zang, Xingxing, Martin, Allison M
• Format: Article
• Language: English
• Subjects: Bone marrow; Brain cancer; Brain tumors; Bupivacaine; CD11b antigen; CD4 antigen; CD40 antigen; CD80 antigen; Cell activation; Cell proliferation; Cells; Cerebellum; Clinical trials; Cold; CTLA-4 protein; Ethylenediaminetetraacetic acid; Flow cytometry; Foxp3 protein; Immune checkpoint inhibitors; Immune system; Immunoglobulins; Immunohistochemistry; Immunoregulation; Immunotherapy; Lymphocytes T; Macrophages; Medical research; Medicine, Experimental; Medulloblastoma; Metastases; Microglia; Myeloid cells; Patients; T cells; Therapeutic targets; Tumor cells; Tumor microenvironment; Tumors
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers16152629

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. 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. Flow cytometry reveals a notable presence of CD45 /CD11b macrophage-like and CD45 /CD11b microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (T ), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45 /CD11b 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. 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.