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.

Keywords: PD-1/PD-L1; adenosine; glioma; immunosuppression; tumor microenvironment.

Figure 1

Immunosuppression in glioblastoma via PD-1/PD-L1 axis and adenosine pathway. Tumor core acquires reduction in the oxygen supply causing a release of high amounts of ATP. This nucleotide acts as a damage-associated molecular pattern (DAMP) and starts immune activation. Extracellular ATP binds to P2 receptors and triggers proinflammatory responses through the induction of cytokines and chemokines. A disbalance in the ATP concentration gradient leads to an upregulation of CD39/CD73 axis, favoring adenosine production. Adenosine is a key molecule that initiates a suppressive immune cell infiltration and drives the activation of PD-1/PD-L1 axis. The immunosuppressive loop is maintained indirectly by ATP release and adenosine signaling, which avoids antitumor defenses, promotes immunosuppressive cell profile, and induces upregulation of immune checkpoints. ATP, adenosine 5′-triphosphate; ADO, adenosine; CD39 or ectonucleoside triphosphate diphosphohydrolase 1, cluster of differentiation 39; CD73 or ecto-5′-nucleotidase, cluster of differentiation 73; DAMP, damage-associated molecular pattern; MDSC, myeloid-derived suppressor cells; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1.