VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma
by
, , , , and
Natalia Muñoz Perez
1,*
,
Juliana M. Pensabene
1,
Phillip M. Galbo, Jr.
1,
Negar Sadeghipour
2,
Joanne Xiu
2,
Kirsten Moziak
1,
Rita M. Yazejian
1,
Rachel L. Welch
1,
W. Robert Bell
3,
Soma Sengupta
4
,
Sonikpreet Aulakh
5,
Charles G. Eberhart
6,
David M. Loeb
1,
Emad Eskandar
1,
Deyou Zheng
1,
Xingxing Zang
1 and
Allison M. Martin
1,* 1
Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
2
Caris Life Sciences, Phoenix, AZ 85040, USA
3
Department of Clinical Pathology & Laboratory Medicine, School of Medicine, Indiana University, 340 West 10th Street Fairbanks Hall, Indianapolis, IN 46202, USA
4
Department of Neurology & Neurosurgery, University of North Carolina at Chapel Hill, 170 Manning Drive, Chapel Hill, NC 27599, USA
5
Department of Internal Medicine, West Virginia University, 64 Medical Center Drive, Morgantown, WV 26506, USA
6
Department of Pathology, Johns Hopkins School of Medicine, 600 N Wolfe St., Baltimore, MD 21287, USA
*
Authors to whom correspondence should be addressed.
Cancers 2024, 16(15), 2629; https://doi.org/10.3390/cancers16152629
Submission received: 14 June 2024
/
Revised: 12 July 2024
/
Accepted: 18 July 2024
/
Published: 24 July 2024
(This article belongs to the Special Issue Challenges and New Strategies in the Management of Pediatric Brain Tumors)
Simple Summary
Immune checkpoint blockade has shown remarkable efficacy across various cancers but has failed to improve outcomes in patients with relapsed medulloblastoma (MB). While it is thought that the cold, immunosuppressive tumor microenvironment of MB accounts for this poor efficacy, the precise mechanisms contributing to immune suppression in this context remain unclear. In this study, we explore the immune landscape of MB using a previously unexplored syngeneic mouse model. Our study demonstrates that this model faithfully recapitulates the cold, immunosuppressive tumor microenvironment observed in human disease. Importantly, our research uncovers mechanisms employed by myeloid cells and tumor cells to evade immune detection while highlighting the therapeutic potential of targeting V-domain Ig Suppressor of T-cell Activation (VISTA), a novel inhibitory immune checkpoint, to enhance anti-tumor immunity.
Abstract
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 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.
