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.
Highlights
Cancer is characterized by genetic instability and heterogeneity in the tumor microenvironment (TME)
Studies on the relationship between purinergic signaling and inflammation show that the ADO pathway and programmed cell death 1 (PD-1)/PD-L1 axis have a close relationship and act together to create a favorable environment for tumor immune evasion
The extracellular ATP (eATP)-adenosine axis has a specific role in pro-tumor immune responses including upregulating the PD-1/PD-L1 axis
Summary
Cancer is characterized by genetic instability and heterogeneity in the tumor microenvironment (TME). One of the major challenges in cancer treatment is to block the multifaceted network of tumor mechanisms that cause immunosuppression and resistance to cell death [1, 2]. Glioblastoma multiforme (GBM) is the most malignant subtype of diffuse glioma, and remains the Immunosuppression in Gliomas most lethal among brain tumors [3, 4]. Genetic and phenotypic variability within GBM present problems for the treatment of these tumors [5, 6]. Despite advances in modern medicine, the prognosis for malignant glioma patients remains just over a year. Several avenues, such as tumor resistance, need to be explored to improve therapeutic approaches [7, 8]. Malignant and host cells create a specific niche, where cellular interactions shape the profile of cytokines and chemokines, favoring pro-tumoral activities [9]
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