Better than hiding: high-grade glioma cells remodel the immune microenvironment to suppress cytotoxic immunity

Abstract Gliomas are aggressive brain tumors that progressively acquire a profound immune-evasive phenotype during malignant evolution. However, the mechanisms driving this transition from immune surveillance to immune tolerance are only partially understood. We used a PDGF-B-driven murine model in which sequential low- and high-grade stages of gliomagenesis can be experimentally identified, allowing us to investigate how immune suppression emerges during malignant progression. In vivo lymphocyte depletion experiments were performed in mice bearing immunogenic low-grade glioma transplants to assess the role of specific immune populations. Transcriptomic profiling and flow cytometry were conducted to characterize tumor–immune interactions and cellular dynamics within the tumor microenvironment were evaluated. Depletion experiments demonstrated that CD4⁺ lymphocytes are essential for initiating immune surveillance and promoting the recruitment of cytotoxic CD8⁺ T cells. Transcriptomic analyses revealed that high-grade glioma cells extensively reprogram surrounding immune populations, inducing a shift toward an immunosuppressive transcriptional state characterized by reduced expression of MHC-II-related genes and attenuated interferon signaling. This remodeling was associated with a marked loss of cytotoxic CD8⁺ T lymphocytes and NK cells, driven by contact-dependent interactions with high-grade glioma cells. Strikingly, high-grade glioma cells also enabled the in vivo engraftment of otherwise non-tumorigenic, immunostimulatory low-grade glioma cells, indicating an active reshaping of the immune microenvironment to enforce tolerance. Overall, our findings suggest that the progression to high-grade glioma relies less on cell-autonomous “stealth” mechanisms and more on the ability to tame and reprogram the immune microenvironment, thereby creating a tolerant, tumor-permissive niche.