Impact of IDH mutations on the immunological landscape of gliomas: a TCGA meta-analysis based on the 2021 WHO classification of brain tumours

Abstract

Mutations in the enzyme isocitrate dehydrogenase genes (mIDH) are currently used to classify diffuse gliomas, the most common malignant primary brain tumours in adults. Additional genetic lesions led to the most recent WHO classification that allows stratification in four tumor entities, mIDH gliomas [Oligodendrogliomas (OD) and Astrocytomas (AA)], and wtIDH gliomas: [Glioblastoma (GBM)-like and GBM]. While mIDH clearly correlates with better prognosis, the role of this mutation in antitumor immunity remains controversial. First, we predicted the level of infiltrating immune and stroma cells by ESTIMATE scores and both were significantly lower in mIDH patients. We also found reduced expression of immunoregulatory genes (PD-LI, PD-1, CTLA-4, IDO1, IL-10, LAG3 and TIM3) in mIDH biopsies (p<0.05, vs. wtIDH). Moreover, PD-L1 exhibited a strong negative correlation with mIDH1 in the whole set of mIDH gliomas (p<0.05). However, within this group, this correlation is completely lost in AA (Spearman r: 0.06) in comparison with OD (Spearman r: -0.46, p<0.05). The analysis of gene signatures of tumor-infiltrating immune cells indicated that lymphocyte populations and antigen presenting cells were downregulated in mIDH tumors (p<0.05, vs. wtIDH). However, once again, we found differences within the mIDH group, suggesting that OD exhibit an even colder immunophenotype than AA. Finally, we analyzed the correlation between the expression of IDH1 and MGMT or ATM, DNA repair enzymes that affect chemo- and radio-resistance, respectively. We found a significantly negative correlation between IDH1 and MGMT that is lost in GBM biopsies. In contrast, IDH1 exhibited a significantly positive correlation with ATM in mIDH gliomas but a negative one in GBM. Our observations suggest that the immune landscape of gliomas not only differs due to mIDH status, but also within glioma subtypes, supporting the idea that the overall effect of this genetic lesion depends on the cellular context.