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

Authors

Ashwani Kesarwani, Amber Neil Griffith, Sonam Verma, Tong Hu, Fei Shu, Amanda De Andrade Costa, Yuping Derek Li, Mridu Kanga, Brett H Herzog, David G DeNardo, Mai T Dang, Jingqin Luo, Pei- Yong-Shi, Xuping Xie, Jun Wang, Lieping Chen, Albert Kim, Peggy Kendall, Michael S Diamond, Milan G Chheda

Published in

Neuro-oncology. Aug 08, 2026. Epub Aug 08, 2026.

Abstract

: 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.
: 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.
: 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 myeloid cells enhanced phagocytosis (CT2A: 25%; SB28: 7%) and T-cell responses (activation: 81%; proliferation: 86.8%).
: Targeting Siglec-15, combined with PD-1 blockade and ZIKV overcomes myeloid immunosuppression and enhances T-cell activation in GBM, promoting durable anti-tumor immunity. These findings support further investigation of this combination therapy.

PMID:
42572170
Bibliographic data and abstract were imported from PubMed on 10 Aug 2026.

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