Alterations of the tumor microenvironment in glioblastoma following radiation and temozolomide with or without bevacizumab

Abstract

Background: The immunosuppressive tumor microenvironment (TME) contributes to the tumor progression and treatment failure. Our previous study demonstrated alterations in the TME during bevacizumab (Bev) therapy in human glioblastoma (GB) specimens obtained from patients who underwent surgical resection. Continuous Bev administration downregulates the expression of programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), suppresses the infiltration of tumor associated macrophages (TAMs) and regulatory T cells (Tregs), and increases cytotoxic T lymphocytes (CTLs) infiltration. However, one may argue that these immunosupportive effects might also be induced by radiation therapy (RT) or temozolomide (TMZ), and they cannot necessarily be attributed to Bev alone.Methods: In the present study, changes in the molecules relevant to the TME were analyzed by immunohistochemistry using paired pre-and post-treatment samples of malignant glioma specimens from 15 patients who received RT and TMZ therapy without Bev. Results:The expression levels of CD34, vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (VEGFR2), HIF-1α, CA9, nestin, CD4, CD8, CD163, PD-1, and PD-L1 were not significantly changed after the treatment with RT and TMZ. However, VEGFR1 expression and the number of Foxp3-positive cells tended to be upregulated and increased after the treatment (P=0.058, P=0.082, respectively). Conclusions:This was the first study to show the alterations of TME following RT and TMZ therapy using paired pre-and post-treatment malignant glioma samples. Long-term treatment of RT and TMZ might worsen immunosuppressive TME in malignant gliomas.

The Presence and Potential Role of ALDH1A2 in the Glioblastoma Microenvironment

“…As therapeutic interventions affect the tumor microenvironment [ 42 , 43 ], we next asked whether the expression of ALDH1A2 was changed upon tumor recurrence. To investigate this, we performed Western blots on matched patient primary and recurrent tumor samples.…”

Macrophages, as a Promising Strategy to Targeted Treatment for Colorectal Cancer Metastasis in Tumor Immune Microenvironment

“…TAMs are one of the causes of tumor angiogenesis and tumor immune escape mechanisms, and targeted treatment of macrophages represents a new challenge and may become a novel strategy for cancer therapy. In the TME, the antiangiogenic drugs bevacizumab and ramucirumab can bind to human VEGF and block its biological activity (143)(144)(145); cetuximab and panitumumab bind to the epidermal growth factor receptor (EGFR), repolarize TAMs from M2-like to M1-like phenotypes, recruit myeloid effector cells such as M1 macrophages and PMN for tumor cell killing by ADCC (147)(148)(149), and inhibit angiogenesis and vascular endothelial permeability (162)(163)(164), and thus block M2 cell infiltration in the inflammatory environment and impede tumor development (165)(166)(167). HER2 is positively expressed in CRC, and some studies have shown that trastuzumab and lapatinib, drugs targeting HER2, can inhibit tumor formation by increasing macrophage levels and phagocytosis, and by increasing the infiltration of immune cells, it exerts a therapeutic effect on CRC metastasis (83,146,150,151).…”

The Landscape of Novel Therapeutics and Challenges in Glioblastoma Multiforme: Contemporary State and Future Directions

“…Additionally, bevacizumab which is used in the treatment of primary and recurrent glioblastoma can lead to diminished infiltrative immune suppressive cells, low PD-1/PD-L1 expression and increased cytotoxic T cells which can alter the efficacy of immunotherapies [ 97 ]. To this end, highlighting the influence of previous medications on TME of glioblastoma and subsequent treatments such as immunotherapy, is imperative when evaluating the efficacy of novel glioblastoma therapeutics [ 98 ].…”