Alterations in the RTK/Ras/PI3K/AKT pathway serve as potential biomarkers for immunotherapy outcome of diffuse gliomas.
Abstract
Diffuse gliomas are the most common malignant brain tumors, and immune checkpoint inhibitors have limited therapeutic effects against this cancer. Three oncogenic pathways are altered in diffuse gliomas: the RTK/Ras/PI3K/AKT signaling, TP53, and RB pathways. Although these pathways may affect the tumor immune microenvironment, their association with immunotherapy biomarkers remains unclear. We used copy number variation and mutation data to stratify patients with specific oncogenic signaling alterations, and evaluated their correlation with predictive immunotherapy biomarkers, including tumor mutation burden (TMB), immune cytolytic activity (CYT), tumor purity, and tumor-infiltrating CD8+ T cells. Immune checkpoint expression and interferon-γ signaling activity were also compared in these samples. We identified differentially expressed genes in three distinct oncogenic pathways. Gene ontology analysis of these genes revealed the involvement of RTK/Ras/PI3K/AKT-associated genes in immune and inflammatory responses. Moreover, significantly elevated TMB, CYT, and numbers of CD8+ T cells and decreased tumor purity were correlated with altered RTK/Ras/PI3K/AKT signaling. Single cell sequencing also confirmed that this tumor subgroup...Continue Reading
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