Targeting the Siglec-sialic acid axis promotes antitumor immune responses in preclinical models of glioblastoma.

Autor: Schmassmann P; Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland., Roux J; Bioinformatics Core Facility, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland.; Swiss Institute of Bioinformatics, 4031 Basel, Switzerland., Buck A; Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, 8091 Zurich, Switzerland., Tatari N; Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland., Hogan S; Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland., Wang J; Cancer Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland., Rodrigues Mantuano N; Cancer Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland., Wieboldt R; Cancer Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland., Lee S; Institute of Molecular Systems Biology, ETH Zurich, 8049 Zurich, Switzerland., Snijder B; Institute of Molecular Systems Biology, ETH Zurich, 8049 Zurich, Switzerland., Kaymak D; Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland., Martins TA; Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland., Ritz MF; Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland., Shekarian T; Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland., McDaid M; Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland., Weller M; Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, 8091 Zurich, Switzerland., Weiss T; Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, 8091 Zurich, Switzerland., Läubli H; Cancer Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland.; Division of Oncology, Department of Theragnostics, University Hospital of Basel, 4031 Basel, Switzerland., Hutter G; Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland.; Department of Neurosurgery, University Hospital of Basel, 4031 Basel, Switzerland.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2023 Jul 19; Vol. 15 (705), pp. eadf5302. Date of Electronic Publication: 2023 Jul 19.
DOI: 10.1126/scitranslmed.adf5302
Abstrakt: Glioblastoma (GBM) is the most aggressive form of primary brain tumor, for which effective therapies are urgently needed. Cancer cells are capable of evading clearance by phagocytes such as microglia- and monocyte-derived cells through engaging tolerogenic programs. Here, we found that high expression of sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) correlates with reduced survival in patients with GBM. Using microglia- and monocyte-derived cell-specific knockouts of Siglec-E, the murine functional homolog of Siglec-9, together with single-cell RNA sequencing, we demonstrated that Siglec-E inhibits phagocytosis by these cells, thereby promoting immune evasion. Loss of Siglec-E on monocyte-derived cells further enhanced antigen cross-presentation and production of pro-inflammatory cytokines, which resulted in more efficient T cell priming. This bridging of innate and adaptive responses delayed tumor growth and resulted in prolonged survival in murine models of GBM. Furthermore, we showed the combinatorial activity of Siglec-E blockade and other immunotherapies demonstrating the potential for targeting Siglec-9 as a treatment for patients with GBM.
Databáze: MEDLINE