The Siglec-sialic acid axis is a target for innate immunotherapy of glioblastoma

In spite of the paradigm shift in cancer therapy that came with the discovery of immune checkpoint inhibitors, current treatment modalities which are predominantly T cell centric, fail to evoke durable tumor rejection in glioblastoma (GBM) patients. Leaving aside the fundamental role innate immune cells play in the tumor microen-vironment (TME), especially in less immunogenic tumors such as GBM.
Upregulation of sialic acid-containing glycans on the cell surface and in the tumor microenvironment (hypersialylation) is a key change in malignant tissue and capable of impacting tumorigenesis by promoting cell invasion and metastatic po-tential. By engaging immunomodulatory sialic acid-binding immunoglobulin-like lectins (Siglecs), tumor hypersialylation can trigger tolerogenic programs in different immune cell types and contributes to the establishment of the immunosuppressive TME.
By targeting inhibitory Siglec-E receptor on GBM-associated microglia (MG) and monocyte-derived cells (MdCs), we show increased tumor cell phagocytosis and improved subsequent T cell activation. Using a poorly immunogenic GBM pre-clinical model, we further demonstrate the synergistic potential of Siglec-E blockade in combined immunotherapies against GBM. Finally, we showcase the translational relevance of Siglec disruption on patient-derived samples.
To explore other tolerogenic programs within the GBM immune TME on a single-cell level, we performed single-cell RNA sequencing (scRNA-seq) on paired biopsies from the tumor center, peripheral infiltration zone and blood of five primary GBM patients. We revealed a regionally distinct transcription profile of microglia (MG) and monocyte-derived macrophages (MdMs) and an impaired activation sig-nature in the tumor-peripheral cytotoxic-cell compartment. Comparing tumor-infiltrating CD8+ T cells with circulating cells identified CX3CR1high and CX3CR1int CD8+ T cells with effector and memory phenotype, respectively, enriched in blood but absent in the TME.
Based on our data, we propose Siglec-E as innate immune checkpoint in GBM-associated MG and MdCs and underscore the value of Siglec blockade in lib-erating innate immune responses to potentiate anti-tumor immunity. Further, our scRNA-seq analysis provides a regionally-resolved mapping of transcriptional states in GBM-associated leukocytes, serving as an additional asset to the research community in their effort to uncover novel therapeutic strategies to combat this fatal disease.