Immunosuppression in Gliomas via PD-1/PD-L1 Axis and Adenosine Pathway

Abstract

Glioblastoma is the most malignant and lethal subtype of glioma. Despite progress in therapeutic approaches, issues with the tumor immune landscape persist. Multiple immunosuppression pathways coexist in the tumor microenvironment, which can determine tumor progression and therapy outcomes. Research in immune checkpoints, such as the PD-1/PD-L1 axis, has renewed the interest in immune-based cancer therapies due to their ability to prevent immunosuppression against tumors. However, PD-1/PD-L1 blockage is not completely effective, as some patients remain unresponsive to such treatment. The production of adenosine is a major obstacle for the efficacy of immune therapies and is a key source of innate or adaptive resistance. In general, adenosine promotes the pro-tumor immune response, dictates the profile of suppressive immune cells, modulates the release of anti-inflammatory cytokines, and induces the expression of alternative immune checkpoint molecules, such as PD-1, thus maintaining a loop of immunosuppression. In this context, this review aims to depict the complexity of the immunosuppression in glioma microenvironment. We primarily consider the PD-1/PD-L1 axis and adenosine pathway, which may be critical points of resistance and potential targets for tumor treatment strategies.

A Novel Oral Arginase 1/2 Inhibitor Enhances the Antitumor Effect of PD-1 Inhibition in Murine Experimental Gliomas by Altering the Immunosuppressive Environment

“…Immune checkpoint inhibitor-based therapies provided an effective strategy to enhance antitumor immune responses in many solid cancers ( 5 ). Programmed cell death 1 (PD-1, CD279), an immune checkpoint surface receptor expressed on lymphocytes, is a mediator of immune suppression in a variety of tumors, including GBM ( 6 ). Binding of PD-1 with its ligands B7-H1 (PD-L1) or B7-DC (PD-L2) induces apoptosis or exhaustion of activated immune cells.…”

P2Y12 Purinergic Receptor and Brain Tumors: Implications on Glioma Microenvironment

“…It is known that the GBM microenvironment is rich in signaling pathways [ 12 ]. Extracellular vesicles (EVs) play a role as mediators of intercellular communication in the TME, which are able to modulate immune responses; however, their function in tumor growth is not clear [ 54 ].…”

“…Furthermore, the glioma treatment has been shown to be involved in increased levels of purine and pyrimidine metabolites, particularly in resistant glioma cells [ 66 ]. The extracellular ATP promotes immune responses by acting on P2 purinergic receptors expressed on both tumor and host cells and also supports an immunosuppressive and proangiogenic environment around the tumor by the generation of adenosine [ 12 , 67 , 68 ].…”

“…Studies have demonstrated that the CXCL12 released by platelets induces leucocyte recruitment to the tumor site, such as macrophages, stimulating tumor growth and angiogenesis. Macrophages in the glioma microenvironment are “plastic” and frequently shape into a tumor-associated phenotype, being a barrier to immune attack [ 12 ]. The expression of endothelial-leucocyte adhesion molecules is also induced by activated platelets expressing interleukin 1 beta (IL-1β) [ 102 ].…”

“…The purinergic system in the TME is complex and plays a role in balance with immune signaling pathways. The half-life of extracellular ATP (eATP) is short because of the quick action of ectoenzymes that convert ATP to adenosine diphosphate (ADP) and then into adenosine, leading to a rich medium for growth-promoting and immunomodulatory factors [ 10 , 11 , 12 , 13 ].…”