Adenosinergic Pathway: A Hope in the Immunotherapy of Glioblastoma

Abstract

Brain tumors comprise different types of malignancies, most of which are originated from glial cells. Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor with a poor response to conventional therapies and dismal survival rates (15 months) despite multimodal therapies. The development of immunotherapeutic strategies seems to be necessary to enhance the overall survival of GBM patients. So far, the immunotherapies applied in GBM had promising results in the primary phases of clinical trials but failed to continue their beneficial effects in later phases. GBM-microenvironment (GME) is a heterogenic and rigorously immunosuppressive milieu wrapping by an impenetrable blood-brain barrier. Hence, in-depth knowledge about the dominant immunosuppressive mechanisms in the GME could foster GBM immunotherapy. Recently, the adenosinergic pathway (AP) is found to be a major player in the suppression of antitumor immune responses in the GME. Tumor cells evolve to metabolize pro-inflammatory ATP to anti-inflammatory adenosine. Adenosine can suppress immune responses through the signaling of adenosine receptors on immune cells. The preclinical results targeting AP in GBM showed promising results in reinvigorating antitumor responses, overriding chemoresistance, and increasing survival. We reviewed the current GBM immunotherapies and elaborated on the role of AP in the immunopathogenesis, treatment, and even prognosis of GBM. We suggest that future clinical studies should consider this pathway in their combination therapies along with other immunotherapeutic approaches.

Tumor-Derived Exosomes: Hidden Players in PD-1/PD-L1 Resistance

“…AR activation contributes to tumor growth and formation of metastases [125,[134][135][136][137], notably by increasing T-cell anergy or promoting T-regs [138,139]. Interestingly, triggering AR can result in an increased expression of immune checkpoints such as CTLA-4, PD-1, LAG-3, and TIM-3 on CD8 + T-cells [140]. Several pre-clinical studies have demonstrated the synergistic effect of anti-PD-1 or anti-PD-L1 treatments in combination with the use of anti-CD73 antibodies.…”

Personalized Immunotherapy in Colorectal Cancers: Where Do We Stand?

“…Neoantigen vaccines are extensively investigated in melanoma and glioblastoma with promising results in increasing patients' survival (173)(174)(175). Given that glioblastoma has a low mutational and neoantigenic burden (8,176,177), these results suggest that neoantigen-based vaccines are effective even in tumors with low mutation rates such as pMMR/MSI-L (64,175). Neoantigen vaccines may improve the infiltration of immune cells into CRCME and increase the immunoscore of tumors, leading to increased tumor responses to ICIs and other immunotherapies (64).…”

Glioblastomas

“… On the left, an illustration of the different cell populations composing glioblastoma and its microenvironment, as well as associated blood-brain barrier disruption. On the right, a summary of the different areas covered by the articles in this Special Issue: GBM cells, stem cells, and preclinical studies [ 2 , 3 , 4 , 5 , 6 ], clinical studies [ 7 , 8 ], immunotherapy and new treatments [ 9 , 10 , 11 , 12 ]. Created with BioRender.com.…”

“…Eleven papers are included in this issue [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ], and they range from in vitro and preclinical studies to clinical studies, and to immunotherapy and new potential treatments for glioblastomas ( Figure 1 ).…”

“…The final four papers in this Special Issue deal with immunotherapy or potentially novel treatments for glioblastomas. Jin et al built on data supporting the adenosinergic pathway (AP) as a major suppressor of antitumor immune responses in the GBM microenvironment [ 9 ]. Tumor cells evolve to metabolize pro-inflammatory ATP to anti-inflammatory adenosine that can suppress immune responses through the signaling of adenosine receptors on immune cells.…”