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In this study, another group of researchers reports a similar idea - that response to therapy in glioblastoma (GBM) may depend just as much on tumor cell state and the surrounding immune environment as on genetic mutations. The study analyzed 181 immune checkpoint inhibitor (ICI)-treated glioblastoma (GBM) samples using bulk DNA and RNA sequencing along with single-nucleus RNA sequencing to understand what predicts response in IDH-wildtype GBM.
The main finding was that the tumor’s baseline cell state, rather than its mutational burden, best predicted outcomes. Tumors with a mesenchymal (MES) subtype had better survival with ICIs compared to non-MES tumors, even though this same subtype did not benefit as much from standard chemoradiation. This MES state was linked to higher immune signaling (HLA class I expression) and more T cell infiltration, consistent with a more inflamed tumor environment. In contrast, overall mutation burden was not predictive, while specific genetic changes such as PDGFRA and CDKN2A were associated with worse outcomes after ICI but not standard therapy.
Long-term analyses suggested that ICI treatment may shift how tumors evolve over time, with selection of resistant subclones and changes away from MES-like states, suggesting that immunotherapy and chemoradiation may push tumors along different evolutionary paths.