Challenges and potential of PD-1/PD-L1 checkpoint blockade immunotherapy for glioblastoma

Abstract

PD-1/PD-L1 checkpoint blockades have achieved significant progress in several kinds of tumours. Pembrolizumab, which targets PD-1, has been approved as a first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with positive PD-L1 expression. However, PD-1/PD-L1 checkpoint blockades have not achieved breakthroughs in treating glioblastoma because glioblastoma has a low immunogenic response and an immunosuppressive microenvironment caused by the precise crosstalk between cytokines and immune cells. A phase III clinical trial, Checkmate 143, reported that nivolumab, which targets PD-1, did not demonstrate survival benefits compared with bavacizumab in recurrent glioblastoma patients. Thus, the combination of a PD-1/PD-L1 checkpoint blockade with RT, TMZ, antibodies targeting other inhibitory or stimulatory molecules, targeted therapy, and vaccines may be an appealing solution aimed at achieving optimal clinical benefit. There are many ongoing clinical trials exploring the efficacy of various approaches based on PD-1/PD-L1 checkpoint blockades in primary or recurrent glioblastoma patients. Many challenges need to be overcome, including the identification of discrepancies between different genomic subtypes in their response to PD-1/PD-L1 checkpoint blockades, the selection of PD-1/PD-L1 checkpoint blockades for primary versus recurrent glioblastoma, and the identification of the optimal combination and sequence of combination therapy. In this review, we describe the immunosuppressive molecular characteristics of the tumour microenvironment (TME), candidate biomarkers of PD-1/PD-L1 checkpoint blockades, ongoing clinical trials and challenges of PD-1/PD-L1 checkpoint blockades in glioblastoma.

Keywords: Glioblastoma multiforme; Nivolumab; Temozolomide; Tumour infiltrating lymphocytes; Tumour mutation load.

Fig. 1

The immunosuppressive mechanism of glioblastoma microenvironment. The immunosuppressive microenvironment of glioblastoma is composed of a variety of immunosuppressive cells and cytokines. The effective immune cells mainly include CD4+ T cells, CD8+ T cells, NK cells, and tumour-inhibiting M1-TAMs, which are in a state of exhaustion or suppression in the microenvironment. The immunosuppressive cells mainly include Tregs, tumourigenic M2-TAMs, myeloid cells, and MDSCs. Tumour cells express high levels of PD-L1 and IDO, downregulate MHC and costimulatory molecules, express/activate STAT3, cause PTEN loss, then reduce the immunogenicity and induce recruitment of Tregs. Tumour cells secrete MICA/B, IL-10, TGF-β, and HLA-E to recruit Tregs and inhibit both T cell and NK cell activity. Through the secretion of diverse chemokines and other factors, such as CCL2, CSF1, MCP-3, CXCL12, CX3CL1, GDNF, ATP, and GM-CSF, the paracrine network signalling between glioblastoma and the TAMs attracts myeloid cells and infiltrates Tregs. Furthermore, tumour cells secrete immunomodulatory cytokines that polarize TAMs to the immunosuppressive M2 phenotype. Immunosuppressive cells, including M2-TAMs, myeloid cells, and MDSCs, secrete a variety of cytokines (IL-6, IL-10, IL-4Ra, FasL, CCL2, PGE2, EGF, VEGF, and MMP9) to suppress the function of cytotoxic T lymphocytes (CTLs) and promote the progression of tumour cells. In addition, Tregs downregulate IL-2 production, inhibit IFN-γ production, and upregulate T_H2 cytokine secretion to inhibit T cell function. TAM: tumor-associated macrophage; MDSC: myeloid-derived suppressor cell; CCL2: chemokine ligand 2; CSF1: colony-stimulating factor 1; MCP-3: monocyte-chemotactic protein-3; GDNF: glial cell-derived neurotrophic factor; GM-CSF: granulocyte-macrophage colony-stumulating factor; KIR: killer cell Ig-like receptor; GITR: glucocorticoid-induced TNFR-related protein; STAT3: signal transducers and activators of transcription; PGE2: prostaglandin E2; EGF: epidermal growth factor; VEGF: vascular endothelial growth factor; MMP9: matrix metalloproteinase-9