CTLA4-Mediated Immunosuppression in Glioblastoma is Associated with the Infiltration of Macrophages in the Tumor Microenvironment

Abstract

Purpose CTLA4, the immune checkpoint, has been widely reported to contribute to immune evasion in anti-tumor activity. The inhibitors of CTLA4 provide a novel strategy to improve the outcome of peripheral cancer, but their clinical effects are limited in glioblastoma (GBM), thus the comprehensive role of CTLA4 needs to be addressed. Patients and Methods A total of 471 GBM cases were enrolled in this study from 5 cohorts. In our works, the Cancer Genome Atlas (TCGA) cohort was divided into the training set, and the Chinese Glioma Genome Atlas (CGGA), REMBRANDT, and GSE84465 cohorts were divided into validation sets. Tissues from our cohort were collected for histopathologic validation. Then, the role of CTLA4 in the TME of GBM was comprehensively investigated. Results Significant differences exist in immunological characteristics between the low and high CTLA4 expression groups. Mutation analysis found different genomic patterns associated with CTLA4 expression. Next, network analysis found the module named c1-1562 including CTLA4 correlated with over survival (OS) in GBM. We also developed a predictive model to calculate the risk score for every GBM case and the risk score was independently related to OS. Furthermore, the expression of CTLA4 was positively related to the infiltration level and function of macrophage in GBM TME based on seven independent algorithms, single-cell RNA-seq data and immunohistochemistry. Conclusion These findings implicate that CTLA4 could serve as a novel target for prognosis and therapy in GBM patients. CTLA4-mediated immune suppression may be attributed to the infiltration of macrophages in the tumor microenvironment.

Phosphoserine phosphatase as an indicator for survival through potentially influencing the infiltration levels of immune cells in neuroblastoma

“…On the one hand, tumor-associated macrophages are closely associated with the tumor malignant progression. It has been reported that the infiltration of macrophages might result in CTLA4-mediated immune suppression and lead to poor prognosis in glioblastoma patients (Guan et al, 2021). Asgharzade et al reported the infiltration of macrophages in metastatic NB (Asgharzadeh et al, 2012).…”

Clinical Characterization and Prognostic Value of TPM4 and Its Correlation with Epithelial–Mesenchymal Transition in Glioma

“…In tumor cells and macrophages, TPM4 expression showed an increasing trend as the WHO grade increased, suggesting that TPM4 abnormality was mainly attributed to tumor progression and tumor-associated macrophage (TAM) infiltration, which was further confirmed in the subsequent pseudotime trajectory analysis. As a critical cell subpopulation of TME, TAMs have been concluded to play a vital role in promoting the genesis and progression of glioma [ 31 , 32 ]. Particularly, M2 polarization of macrophages is significantly associated with aggressive progression across different malignancies, especially with immune escape of tumor cells.…”

Immunotherapy in glioblastoma treatment: Current state and future prospects

“…Conversely, the expression of the CD95 (Fas) ligand by GBM cells can also attenuate immune attack through the induction of CD95-Dependent apoptosis in infiltrating lymphocytes[ 69 ]. In turn, CTLA-4 is also an important ICs due to its capacity to compete with CD28 for binding to costimulatory molecules (CD80 and CD86) on antigen-presenting cells, thereby precluding the activation of T cells[ 67 , 68 , 70 , 71 ]. Lastly, indoleamine 2,3-dioxygenase 1 (IDO) and Lectin-like transcript-1 (LLT-1), are known to increase intratumoral Treg and myeloid-derived suppressor cells, and to repress NK cell activity, respectively[ 72 , 73 ].…”