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

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.

Gene expression analysis suggests immunosuppressive roles of endolysosomes in glioblastoma

“…Of note, the set of five genes described above ( CTSD, CTSZ, FUCA1, GRN , and IFI30 ) were among those that were significantly elevated in the immunosuppressive SIGLEC9 + TAMs 15 . Together with previous findings 15,25 , the results from these analyses suggest that endolysosomes likely play instrumental roles in conferring GBM resistance to immunotherapy.…”

“…While the findings above suggest the roles of endolysosomes in GBM pathogenesis, particularly in shaping GBM’s immunosuppressive microenvironment, they raise the question of the roles of endolysosomes in the context of GBM resistance to immunotherapy. To address this question, we took advantage of the recent findings that subsets of SIGLEC9 + TAMs dampen GBM’s response to immunotherapy 15,25 . We specifically focused on two subsets of SIGLEC9 + TAMs that were found to be highly plastic and immunosuppressive ( SIGLEC9 + MARCO + TAMs, cluster C9, and SIGLEC9 + SEPP1 + TAMs, cluster C2) 15 , and examined genes that were upregulated in these two populations of TAMs (versus their respective SIGLEC9 - counterparts).…”

Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker

“…Second, we treated the animals with anti-CD47 antibody clone B6H12 which might have lower efficacy than the antibody H5F9 used in clinical trials - leading to inferior antitumor activity. However, systemic anti-CD47 mono-treatment failed to yield substantial survival benefits in aggressive brain tumor models in several studies 70,71 . Third, we did not perform continuous local maintenance dosing of anti-CD47 antibodies which might mask optimal efficacy of anti-CD47 treatment.…”

Antibody-lectin chimeras for glyco-immune checkpoint blockade

“…studies indicate that upregulation of cell-surface sialoglycans allows tumors to engage inhibitory Siglec receptors on immune cells and evade immune surveillance [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] . Taken together, glycoimmune checkpoints are emerging as attractive targets for cancer immunotherapy.…”

“…This approach uniquely enables blockade of immunomodulatory glycans at nanomolar concentrations agnostic of their specific identities. We demonstrate proof-of-concept of the AbLec platform through the development and characterization of AbLecs combining tumor-targeting antibodies with decoy receptor domains from Siglecs-7 and -9, which have been shown to mediate immune suppression in multiple cancers [11][12][13][16][17][18][19][20][21][22][23][24][25][26][27] . We show that tumor-targeting AbLecs enhance antibody-dependent phagocytosis and cytotoxicity of cancer cells by multiple primary immune cell subsets compared to the parent monoclonal antibody.…”