Recurrent glioblastoma remains uniformly lethal despite maximal surgery, radiation, and chemotherapy, and immunotherapies that succeed in other cancers have largely failed in this setting. Targeting a single checkpoint is often insufficient due to the profoundly immunosuppressive tumor microenvironment and the ability of glioblastoma to engage multiple, redundant escape pathways. This ASPIRE Award addresses the need for an upstream regulator that coordinates multiple immunosuppressive programs and can be leveraged to render immunotherapy effective in recurrent disease.
The team has identified the interferon-stimulated long noncoding RNA INCR1 as a central node induced by immune activation that promotes expression of several immunosuppressive factors, including PD-L1 and IDO1, via interactions with RNA-binding proteins and interferon signaling intermediates. They will rigorously validate antisense oligonucleotides (ASOs) targeting INCR1 by quantifying on-target knockdown and downstream immunosuppressive gene modulation across panels of patient-derived glioblastoma cells, and by testing whether INCR1 silencing enhances immune-mediated tumor killing in co-culture models. Transcriptomic profiling will be used to define selectivity and distinguish on-target effects from off-target or innate inflammatory responses. By repurposing a clinically established ASO modality to disable a noncoding RNA “hub” of immune escape, this work could enable more durable responses to immunotherapies for patients with recurrent glioblastoma.