Modeling immunoediting in glioma progression

The occurrence of a mutual reshape of tumor cell and immune system during tumor progression is a widely accepted notion in many different cancers including gliomas. The importance of this phenomenon in shaping glioma progression and the mechanisms governing it, however, are not fully elucidated. We used a well-characterized glioma model, based on somatic gene transfer of PDGF-B. Novel custom image-analysis tools allowed us to define the in vivo immune cell composition of gliomas at different stages of progression. Complementing this, genome-wide transcriptomics on purified tumor cells coherently pointed to the progression-related reorganization of glioma-immune system interactions. A set of in vivo tumor-propagating experiments in immune-competent or -deficient hosts allowed dissecting stage-specific roles of the immune system in shaping acquisition of malignancy in this model of glioma progression. Specifically, we show that the inability of cells from low-grade gliomas to propagate upon grafting in the brain of syngeneic immunocompetent mice, positively correlates with the abundance of infiltrating CD8+ lymphocytes in donor tumors and correlates with a highly immunostimulatory transcriptional profile, comprising genes typically involved in the immune response and inflammation, cytokine production and lymphocyte chemotaxis. Importantly, during tumor progression glioma cells downregulate these genes and the composition of their immune infiltrate accordingly shifts towards a pro-tumorigenic phenotype. Challenging low-grade and immune-stimulatory gliomas with grafting into immunodeficient (NOD/SCID) hosts revealed the crucial role of the adaptive immune system in constraining glioma progression. Finally, we observed that although progression still takes place in NOD/SCID mice, it is apparently slower, likely due to a far milder selection and reinforcing the view that the immune system constitutes a central player in shaping the rate of glioma progression.