Siglec-15 and PD-1 checkpoint blockade in combination with oncolytic Zika virus infection confers protection against immune-resistant gliomas

作者：Kesarwani A, Griffith AN, Verma S, Hu T, Shu F, De Andrade Costa A, Li YD, Kanga M, Herzog BH, DeNardo DG, Dang MT, Luo J, Yong-Shi P, Xie X, Wang J, Chen L, Kim A, Kendall P, Diamond MS, Chheda MG · 发表于：Neuro-oncology · 年份：2026 · DOI：10.1093/neuonc/noag186 · 研究领域：CT2A、SB28、Siglec-15、Zika virus、glioblastoma

BACKGROUND: : The glioblastoma (GBM) immunosuppressive tumor microenvironment is a clinical challenge. Oncolytic Zika virus (ZIKV) has emerged as a promising therapy, targeting treatment-resistant glioma stem cells, stimulating CD8+ T-cell-mediated immunity and extends survival in preclinical models but myeloid cell-driven immunosuppression persists. An antagonist of Siglec-15, a myeloid immune checkpoint molecule, is in a phase II trial for non-small cell lung cancer, but its role in CNS malignancies remains unclear. METHODS: : We evaluated Siglec-15 expression in human GBM samples using flow cytometry, mass cytometry, and immunofluorescence, as well as a public database. Using syngeneic glioma models, we tested a blocking antibody against Siglec-15, and Siglec-15 knock out mice, alongside ZIKV and anti-PD-1 therapies. We performed survival studies and analyzed immune responses, T-cell proliferation and phagocytosis, and tumor rechallenge. RESULTS: : Siglec-15 was expressed by human GBM myeloid (16-22%) and tumor (18-19%) cells, and higher expression was associated with shorter survival. In CT2A-bearing mice, ZIKV + anti-Siglec-15 increased long-term survival to 60% (vs. 40% with ZIKV alone), rising to 83% with anti-PD-1 treatment. Triple therapy in SB28 bearing mice yielded 76% long-term survivor rate with 1.7-fold higher CD8+ T-cell activation. Rechallenged mice showed 11-fold expansion of brain resident/effector memory CD8+ T-cells and 80% survival. Siglec-15 loss on my...