Schmassmann et al. showed that the siglec–sialic acid axis acts as an innate immune inhibitory pathway, and is correlated with poor survival in GBM patients. Deletion of Siglec-E, the mouse homolog of Siglec-9, in microglia- and monocyte-derived cells, or reduction of siglec ligands on tumor cells increased tumor cell phagocytosis, antigen cross-presentation, and pro-inflammatory cytokine production, which led to efficient T cell priming and enhanced intratumoral CD8+ T cell responses. Siglec–sialic acid axis inhibition showed synergistic activity with combinatorial immunotherapies in a preclinical GBM model, and induced immune activation in patient-derived explant cultures.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (2) Bioinformatics Core Facility, Department of
Author Info: (1) Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (2) Bioinformatics Core Facility, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. Swiss Institute of Bioinformatics, 4031 Basel, Switzerland. (3) Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, 8091 Zurich, Switzerland. (4) Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (5) Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (6) Cancer Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (7) Cancer Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (8) Cancer Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (9) Institute of Molecular Systems Biology, ETH Zurich, 8049 Zurich, Switzerland. (10) Institute of Molecular Systems Biology, ETH Zurich, 8049 Zurich, Switzerland. (11) Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (12) Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (13) Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (14) Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (15) Brain Tumor Immunotherapy Lab, Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (16) Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, 8091 Zurich, Switzerland. (17) Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, 8091 Zurich, Switzerland. (18) 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. (19) 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.
