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Lookup NU author(s): Dr Dean Thompson, Anya FletcherORCiD, Dr Stacey RichardsonORCiD, Dr Rebecca HillORCiD, Professor Steven CliffordORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2026. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Background: Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesized that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets. Methods: We analyzed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the TME. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single-cell RNA-sequencing data. These interactions were validated across RNA and proteomic datasets. Their functional significance was empirically demonstrated in newly developed immunocompetent models of recurrent medulloblastoma that closely recapitulate the human disease. Results: We observed a shift toward a heightened immunosuppressive TME at relapse. Using our algorithm, we identified biologically significant receptor-ligand interactions, most notably MIF-CD74, constitutively expressed at RNA and protein levels across medulloblastoma subgroups, at diagnosis and relapse. Disrupting MIF-CD74 interactions led to significant alterations in the tumor microenvironment, highlighting its functional significance. Conclusions: Our multifaceted approach identified key tumor-immune interactions in medulloblastoma. Among these, MIF-CD74 was validated as a targetable interaction, demonstrating the utility of our integrative approach for identifying novel therapeutic targets across multiple tumor types.
Author(s): Draper B, You Z, Thompson D, Guo X, Morcavallo A, Chillon Pino D, Lorenzo Gido Nery C, Shrestha S, Bowers CE, Himsworth C, Delaidelli A, Remeniuk B, Morlando S, Wade B, Gordon F, Sanchez-Corrales Y, Hopkins B, Monteiro N, Locke D, Liu M, Diaz JT, Greenslade K, Martins da Costa B, Barker K, Kwok C, Ogunbiyi O, Fletcher A, Richardson S, Custodia C, Roque R, Jackson T, Barfoot R, Castellano S, Hill RM, Saulnier O, Jacques TS, Taylor MD, Faria CC, Ayrault O, Sorensen PH, Anderson J, Chesler L, Frank Huang L, Clifford SC, Donovan LK
Publication type: Article
Publication status: Published
Journal: Neuro-Oncology
Year: 2026
Volume: 28
Issue: 5
Pages: 1316-1334
Print publication date: 01/05/2026
Online publication date: 06/02/2026
Acceptance date: 27/01/2026
Date deposited: 01/06/2026
ISSN (print): 1522-8517
ISSN (electronic): 1523-5866
Publisher: Oxford University Press
URL: https://doi.org/10.1093/neuonc/noag020
DOI: 10.1093/neuonc/noag020
Data Access Statement: Deconvolution analyses: No custom code was used in this study. Open-source algorithms were used as detailed in the methods section. Details on how these algorithms were used are available from the corresponding authors upon request. CellCrossTalker tool: Original codes used for the study will be available at: Roosevelt-PKU/Tumor-immune-stromal-interaction. This study did not generate new unique reagents.
PubMed id: 41652893
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