Work

697 Sex-biased macrophage polarization and CD8 + T cell suppression downstream of Yap1-CD276 signaling in medulloblastoma

Year: 2026

Type: conference-abstract

Abstract: Background Medulloblastoma (MB), the most common pediatric brain malignancy, exhibits a significant sex bias, with males experiencing higher incidence and worse clinical outcomes across all subtypes. We previously identified a sex-biased role for the oncogene Yap1 in Sonic Hedgehog (SHH) MB, where Yap1 deletion preferentially extends survival in males by attenuating CD276 (B7-H3) expression and function.1 Here, we investigate the mechanistic basis of this sex-specific immune evasion and evaluate the therapeutic potential of targeting CD276 using chemically self-assembled nanorings (CSANs).Methods High-parameter flow cytometry and single-cell RNA sequencing (scRNA-seq) were used to profile the MB immune microenvironment following Yap1 deletion. In vivo CD8+ T cell depletion was performed to assess functional contributions to survival. Therapeutic efficacy was evaluated using systemic administration of CD276-targeting CSANs.Results Yap1 loss induced a major shift in tumor-associated macrophage (TAM) phenotype. In Yap1 wild-type tumors, TAMs exhibited an immunosuppressive M2-like state characterized by high Cd39 and Mrc1 expression. While macrophage abundance was comparable between sexes, scRNA-seq revealed a sex-specific divergence in polarization, with TAMs in Yap1-deleted female tumors retaining higher Cd39 expression. Consistent with these findings, Yap1 deletion drove divergent T cell responses, with increased cytotoxic CD8+ T cell infiltration in males and enrichment of regulatory T cells and exhausted CD8+ T cells in females. CD8+ T cell depletion completely abrogated the male survival advantage, demonstrating their functional importance. CD276-targeting CSANs phenocopied the male-biased survival benefit, significantly increasing T cell infiltration and slowing tumor progression only in male models.Conclusions Yap1 promotes male-biased MB progression through convergent regulation of CD276-dependent CD8+ T cell suppression and sex-specific macrophage polarization. These findings reveal multi-layered sex differences in the tumor immune landscape and support CD276-targeting nanorings as a precision immunotherapy strategy for high-risk MB.Acknowledgements This study was supported by funding from the American Brain Tumor Association Discovery Award, NIH 1R01NS121405-01 and the Department of Defense W81XWH-14-1-0115 to KY, and The Jackson Laboratory Cancer Center fund (P30CA034196) to JG, NCI R01CA247681 to CRW, and the Department of Defense Horizon Award CA191052 to NAEthics Approval Mice were housed and handled in accordance with the protocols and procedures approved by the Houston Methodist Reasearch Istitute’s Institutional Animal Care and Usage Committees (#IS00007141).Reference Abdelfattah N, et al. Male-biased Yap1-Cd276/B7-H3 axis for immune evasion in medulloblastoma. Cancer Cell 2026;44:760–776 e768. https://doi.org:10.1016/j.ccell.2026.01.005

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0697