PD-L1/PD-1 Axis in Glioblastoma Multiforme

Abstract

Glioblastoma (GBM) is the most popular primary central nervous system cancer and has an extremely expansive course. Aggressive tumor growth correlates with short median overall survival (OS) oscillating between 14 and 17 months. The survival rate of patients in a three-year follow up oscillates around 10%. The interaction of the proteins programmed death-1 (PD-1) and programmed cell death ligand (PD-L1) creates an immunoregulatory axis promoting invasion of glioblastoma multiforme cells in the brain tissue. The PD-1 pathway maintains immunological homeostasis and protects against autoimmunity. PD-L1 expression on glioblastoma surface promotes PD-1 receptor activation in microglia, resulting in the negative regulation of T cell responses. Glioblastoma multiforme cells induce PD-L1 secretion by activation of various receptors such as toll like receptor (TLR), epidermal growth factor receptor (EGFR), interferon alpha receptor (IFNAR), interferon-gamma receptor (IFNGR). Binding of the PD-1 ligand to the PD-1 receptor activates the protein tyrosine phosphatase SHP-2, which dephosphorylates Zap 70, and this inhibits T cell proliferation and downregulates lymphocyte cytotoxic activity. Relevant studies demonstrated that the expression of PD-L1 in glioma correlates with WHO grading and could be considered as a tumor biomarker. Studies in preclinical GBM mouse models confirmed the safety and efficiency of monoclonal antibodies targeting the PD-1/PD-L1 axis. Satisfactory results such as significant regression of tumor mass and longer animal survival time were observed. Monoclonal antibodies inhibiting PD-1 and PD-L1 are being tested in clinical trials concerning patients with recurrent glioblastoma multiforme.

Keywords: GBM; PD1; PD1 ligand; glioblastoma multiforme.

Figure 1

Immunological modulation induced by glioblastoma multiforme (GBM) cells. Secretion of programmed cell death ligand 1 (PD-L1) inhibits the immune attack, blocking T cells responses. PD-1: programmed death-1, major histocompatibility complex: MHC, T-cell receptor: TCR, antigen-presenting cell: APC.

Figure 2

GBM induction of PD-L1 secretion. Multiple activation pathways (TLR, EGFR, IFNAR, IFNGR) promoting PD-L1 expression. 1. Toll-like receptors (TLR) pathway: pathogen-associated molecular patterns (PAMPs), NECROSIS, heat shock proteins (HSP) as activators of TLR myeloid differentiation factor 88 (MyD88)-dependent pathway signaling through TRAF6/MEK/ERK/NF-κB. 2. Epidermal growth factor (EGFR) pathway: TGFα/EGF/VGF/MUTATION OF RECEPTOR as activators of EGFR pathway signaling through MEK/ERK (STAT-1)/NF-κB. 3. IFNAR pathway: interferon (IFN)alfa, IFNbeta as activators of IFNAR pathway signaling through MXA gene transcription, forming nonclassical MHC, promoting PD-1L transcription, and the induction of endogenous interferons. 4. IFNGR pathway: IFNgamma as an activator of IIFNGR pathway signaling through JAK/STAT-1/MEK/ERK/IRF-1 and PI3K/PIP3/Akt/mTOR/S6K1, with a regulatory function over transcribed PD-1L mRNA.