The Prognostic and Therapeutic Value of PD-L1 in Glioma

Abstract

Glioma is the most common type of primary brain tumors. After standard treatment regimen (surgical section, radiotherapy and chemotherapy), the average survival time remains merely around 14 months for glioblastoma (grade IV glioma). Recent immune therapy targeting to the immune inhibitory checkpoint axis, i.e., programmed cell death protein 1 (PD-1) and its ligand PD-L1 (i.e., CD274 or B7-H1), has achieved breakthrough in many cancers but still not in glioma. PD-L1 is considered a major prognostic biomarker for immune therapy in many cancers, with anti-PD-1 or anti-PD-L1 antibodies being used. However, the expression and subcellular distribution of PD-L1 in glioma cells exhibits great variance in different studies, severely impairing PD-L1's value as therapeutic and prognostic biomarker in glioma. The role of PD-L1 in modulating immune therapy is complicated. In addition, endogenous PD-L1 plays tumorigenic roles in glioma development. In this review, we summarize PD-L1 mRNA expression and protein levels detected by using different methods and antibodies in human glioma tissues in all literatures, and we evaluate the prognostic value of PD-L1 in glioma. We also summarize the relationships between PD-L1 and immune cell infiltration in glioma. The mechanisms regulating PD-L1 expression and the oncogenic roles of endogenous PD-L1 are discussed. Further, the therapeutic results of using anti-PD-1/PD-L1 antibodies or PD-L1 knockdown are summarized and evaluated. In summary, current results support that PD-L1 is not only a prognostic biomarker of immune therapy, but also a potential therapeutic target for glioma.

Functions and clinical significance of circular RNAs in glioma

“…PD-1/PD-L1 checkpoint blockade represents a promising target strategy for several types of tumours, including glioma. The report from Chen indicated that PD-L1 modulated immune cell infiltration in glioma microenvironment (TME) and served as signaling protein control multiple pathways including STAT3, PI3K/AKT/ mTOR, Ras/ERKsignaling pathways [126]. However, based on low immunogenic responses and immunosuppressive microenvironment of glioblastoma, targeting PD-1/PD-L1 checkpoint is inefficiency mainly attributing to the tumor TME, such as various genomic subtypes or molecular profiles although upregulated PD-L1 is a prognostic biomarker of immune therapy on glioblastoma cells [126,127].…”

HSP70/IL-2 Treated NK Cells Effectively Cross the Blood Brain Barrier and Target Tumor Cells in a Rat Model of Induced Glioblastoma Multiforme (GBM)

“…A follow-up study demonstrated the cytotoxicity enhancement of TKD (antigenic component of HP70)/IL-2 activated NK cells by PD-1 blocker stimulation, which resulted in local tumor control in immunodeficient and/or immunocompetent mice, in GBM and lung cancer models [47]. However, the expression of PD-1 on GBM cells is highly questionable [48]. On the other hand, GBM represents an immunosuppressive microenvironment characterized by low immunogenic responses.…”

Immune checkpoint inhibitors for the treatment of glioblastoma: Where we are

“…Despite the notable strides forward in immunotherapy as a whole and seemingly promising results in preclinical studies, clinical data have not yet yielded significant improvements in GBM therapy, as most studies reported significant effects in only a select few individuals. [17][18][19][20] This dissonance indicates potential deficiencies in clinical models, as the differing immune systems of mice and humans may distort reliable predictability between preclinical and clinical results. This issue could be partially resolved by means of better animal models or by further advancing personalized drug-screening and treatment options for GBM patients.…”

“…[18] Preclinical studies describe PD-L1 antibody therapy to be effective in animal models and to be a potential future direction in GBM therapy, though improvement of PD-1/PD-L1 immunotherapy in GBM is largely reliant on accumulation of clinical data. [19] Others describe significant relationships between high PD-L1 expression, high efficacy with PD-1/PD-L1 inhibition, and high patient mortality rate, potentially warranting these treatments for brain gliomas in clinical cases. [20] One ongoing clinical study has revealed that anti-PD-L1 monotherapy Durvalumab appears to be well tolerated in patients and shows significantly durable activity in a subset of Bevacizumab-naive recurrent GBM patients.…”