190P - Immune-related roles of B7H3 in glioblastoma

Background

Glioblastoma is the most frequent and aggressive primitive brain cancer, associated with dreadful prognosis. This project focuses on a protein called B7H3, member of the B7 « immune checkpoint » protein family. Two isoforms of B7H3 protein (i.e. 2Ig and 4Ig) are produced by alternative splicing and expressed at the cell membrane. Of note, the ectodomain of B7H3 exists as a soluble protein. B7H3 expression in several cancers is associated with poorer prognosis and increased aggressiveness, however its precise role in immune cell modulation in the context of glioblastoma remains elusive.

Methods

Using a murine glioblastoma cell line (CT2A), we allografted immunocompetent mice with CT2A glioma cells overexpressing (OE) the 2Ig isoform of B7H3 (vs cells with control vector). We also engineered a human cell line (U87 OE 2Ig B7H3 vs control vector) to decipher the role of the B7H3 protein on immune cell modulation. Finally patient-derived glioblastoma stem-like cells (GSCs) were used for additional in vitro experiments.

Results

We observed a slight increase in survival in CT2A OE-B7H3 mice, which surprisingly indicated a tumor suppressive effect. We are currently reproducing the experiment using another murine cell line (GL261). Conversely, in vitro coculture experiments revealed no impact of B7H3 on T cell activation or apoptosis, but preliminary results suggest that B7H3 lowers T cell proliferation in vitro. We showed that patient-derived GSCs release soluble B7H3 in the extracellular space and is especially found on extracellular vesicles (EVs).

Conclusions

These results suggest that B7H3 may exert diverse functions in different aspects of glioblastoma immunogenicity. We are exploring the roles of B7H3 isoforms as well as the role it could play on glioblastoma cell-derived EVs, to understand its impact on the immune system.

Legal entity responsible for the study

The authors.

Funding

FNRS, Télévie, Fondation Léon Frédéricq.

Disclosure

G. Jerusalem: Financial Interests, Personal, Advisory Board: Novartis, Roche, Pfizer, BMS, Lilly, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, BMS, Lilly, AstraZeneca, Seagen; Financial Interests, Personal, Steering Committee Member: Novartis, AZ/Daiichi Sankyo, BMS; Financial Interests, Institutional, Local PI: Novartis, Roche, Syneos Health, Iqvia, TRIO, Bayer, MSD, IBCSG, PRA, Eli Lilly, PPD, Theradex, ABCSG, Modra, AstraZeneca, Odonate Therapeutics, BMS, ICON, Boeringer, Quintiles, Pfizer, Lilly, Daiichi Sankyo, Seagen, MedImmune; Non-Financial Interests, Personal, Member: ASCO, BSMO; Other, Personal, Other, Medical writer support: MedImmune, Novartis, Roche, Lilly, Amgen, BMS, AstraZeneca, Merck, Pfizer; Other, Personal, Other, Support for attending meetings and/or travel: Novartis, Lilly, BMS, Roche, Amgen, AstraZeneca, Pfizer. All other authors have declared no conflicts of interest.