Research Paper Volume 13, Issue 11 pp 15444—15458

Alterations in the RTK/Ras/PI3K/AKT pathway serve as potential biomarkers for immunotherapy outcome of diffuse gliomas

Song Han1, *, , Peng-Fei Wang1, *, , Hong-Qing Cai1,2, *, , Jing-Hai Wan2, , Shou-Wei Li1, , Ze-Huan Lin3, , Chun-Jiang Yu1, &, , Chang-Xiang Yan1, ,

  • 1 Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, China
  • 2 Department of Neurosurgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China
  • 3 Grade 2018, Medical College, Qingdao University, Qingdao, China
* Equal contribution and Co-first author

Received: November 20, 2020       Accepted: May 11, 2021       Published: June 8, 2021
How to Cite

Copyright: © 2021 Han et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: 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.

Methods: 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.

Results: 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 had increased immune checkpoint expression and interferon-γ signaling activity. Immune phenotyping based on the presence of CD274 and TMB or CD274 and CD8 T+ cells indicated that tumors with altered RTK/Ras/PI3K/AKT pathways represent a beneficial subtype and are associated with improved survival.

Conclusion: Altered RTK/Ras/PI3K/AKT signaling and immunotherapy biomarkers are strongly correlated in gliomas. Gliomas with altered expression of RTK/Ras/PI3K/AKT pathway components may be sensitive to immunotherapy. A combination of small-molecule kinase inhibitors and immunotherapy is proposed for this subgroup of tumors.


CNS: central nervous system; LGG: lower grade gliomas; GBM: glioblastomas; GO: gene ontology; GSVA: gene set variation analysis; OS: Overall survival; PD-L1: programmed death-ligand 1;TME: tumor microenvironment; PI3K: phosphatidylinositol-3-OH kinase; CYT: immune cytolytic activity; GSEA: gene set enrichment analysis; ssGSEA: single-sample gene set enrichment analysis; GZMA: granzyme A; PRF1: perforin 1; ATRX: ATRX chromatin remodeller; TCGA: The Cancer Genome Atlas dataset.