The occurrence of a mutual reshape of tumor cell and immune system during tumor progression is a widely accepted notion in 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 and novel custom image-analysis tools to define the in vivo immune cell composition 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. We show that the inability of low-grade glioma cells 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. 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, immune-stimulatory, gliomas with grafting into immunodeficient hosts revealed the crucial role of the adaptive immune system in constraining glioma progression. Finally, we observed that although progression still takes place in immunodeficient mice, it is apparently slower, likely due to a far milder selection.

modeling immunoediting in glioma progression

I. Appolloni;F. Alessandrini;D. Marubbi;E. Gambini;D. Reverberi;D. Ceresa;P. Malatesta.
2018

Abstract

The occurrence of a mutual reshape of tumor cell and immune system during tumor progression is a widely accepted notion in 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 and novel custom image-analysis tools to define the in vivo immune cell composition 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. We show that the inability of low-grade glioma cells 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. 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, immune-stimulatory, gliomas with grafting into immunodeficient hosts revealed the crucial role of the adaptive immune system in constraining glioma progression. Finally, we observed that although progression still takes place in immunodeficient mice, it is apparently slower, likely due to a far milder selection.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11567/920247
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