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

Autor: Muñoz Perez N; Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA., Pensabene JM; Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA., Galbo PM Jr; Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA., Sadeghipour N; Caris Life Sciences, Phoenix, AZ 85040, USA., Xiu J; Caris Life Sciences, Phoenix, AZ 85040, USA., Moziak K; Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA., Yazejian RM; Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA., Welch RL; Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA., Bell WR; Department of Clinical Pathology & Laboratory Medicine, School of Medicine, Indiana University, 340 West 10th Street Fairbanks Hall, Indianapolis, IN 46202, USA., Sengupta S; Department of Neurology & Neurosurgery, University of North Carolina at Chapel Hill, 170 Manning Drive, Chapel Hill, NC 27599, USA., Aulakh S; Department of Internal Medicine, West Virginia University, 64 Medical Center Drive, Morgantown, WV 26506, USA., Eberhart CG; Department of Pathology, Johns Hopkins School of Medicine, 600 N Wolfe St., Baltimore, MD 21287, USA., Loeb DM; Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA., Eskandar E; Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA., Zheng D; Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA., Zang X; Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA., Martin AM; Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2024 Jul 24; Vol. 16 (15). Date of Electronic Publication: 2024 Jul 24.
DOI: 10.3390/cancers16152629
Abstrakt: Background: 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 CD45 hi /CD11b hi macrophage-like and CD45 int /CD11b int microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (T regs ), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45 hi /CD11b hi 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.
Databáze: MEDLINE
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