Study of tumor infiltrating immune CELLS and vasculature in human gliomas: Differences in IDH1/2 mutant versus IDH1/2WT tumors.

Abstract

2030 Background: Gliomas harboring mutations in IDH1/2 show a higher overall survival time than “wild type” (wt) tumors. Although the clinical aspects are well described, little is known about the underlying mechanisms by which these mutations generate such a difference in the clinical course. Our group has recently described that IDH1/2 mutations induce a distinct vascular phenotype in the tumors, with less blood-brain barrier (BBB) leakage than the IDH1/2 wt gliomas (In Press, DOI:10.1101/541326). Methods: Prospective study analyzing a cohort of 20 patients with primary gliomas resected in one institution. Samples were obtained in the first surgery and 12 IDHmut and 8 IDHwt gliomas were included. Immune infiltration was analysed by flow cytometry and vasculature by inmunohistochemistry. For molecular biology studies, western blots were performed with Mini-PROTEAN system. Proteins were visible by enhanced chemoluminescence. Results: We show that the immune component also differentiates these two pathologies. There is significantly less immune infiltration in IDH1/2 mutant gliomas. Within the CD45 subset, IDH1/2 mutant gliomas have a reduced proportion of T lymphocytes with a different T cell exhaustion profile and an increased proportion of CD11b+ cells in comparison to IDH1/2 wt cases. Myeloid compartment distribution is also different in these two types of tumors, showing an augmented proportion of the M2 (CD206+) and the neutrophil subsets in IDH1/2 wt gliomas. Moreover, a higher proportion of CD45 PDL1+ was present in the IDH1/2 wt tumors samples. The analysis of the vasculature showed an increase density and the lumen size of the vessels of the IDH1/2 wt compared to the IDH1/2 mutant gliomas which correlate with changes in the immune profile. The biochemical analysis showed that there is an increment in EGFR and PDGFR activity in the IDH wt gliomas that is related with more vascular aberrations and higher CD45 infiltrate. This suggests that EGFR and PDGFR are the key regulators of the tumor microenvironment. Conclusions: To understand the matching between the immune infiltration and vasculogenesis is relevant for interpreting data coming from the clinical trials with checkpoints inhibitors. At the time abstract submission survival analysis is not yet available due to the short time of follow-up but in May 2019, the number of expected events for analysis will be reached.