Exosomes in plasma of glioma patients hold promise as biomarkers of prognosis. We aimed to determine whether changes in total exosomal protein and mRNA expression levels could serve as surrogate markers of immunological and clinical responses in glioma patients receiving antitumor vaccines. Exosomes were isolated from pre/post-vaccine plasma specimens in 20/22 patients enrolled in a phase I/II trial with the antitumor vaccine. Exosomal protein content was analyzed and mRNA expression levels for 24 genes were simultaneously assessed by qRT-PCR. Pre-to postvaccination changes in exosomal protein and DCt values were correlated with immunological and clinical responses and survival using Spearman rank statistics and hazard ratios (HR). Exosomal protein levels positively correlated (p < 0.0043) with the WHO tumor grade at diagnosis. Protein levels were lower in post-vs. pre-vaccination exosome fractions. Post-therapy increases in tumor size were associated with elevations in exosome proteins in glioblastoma but not always in anaplastic astrocytoma (AA). Only exosomal DCt values for IL-8, TIMP-1, TGF-b and ZAP70 were significant (p < 0.04 to p < 0.001). The DCt for IL-8 and TGF-b mRNA positively correlated with post-vaccine immunologic responses to glioma antigens, while DCt for TIMP-1 mRNA was negatively correlated to DCt for IL-8 and TGF-b. Only DCt for IL-8 weakly correlated with OS and time to progression (TTP). In post-vaccine exosomes of the longest surviving patient with AA, mRNA for PD-1 was persistently elevated. Protein and mRNA expression levels for immune-related genes in plasma exosomes were useful in evaluating glioma patients' response to vaccination therapy.

The adenosinergic pathway plays an important role in cancer progression. Aside from regulating functions of tumor cells and tissue cells present in the tumor microenvironment, extracellular adenosine is an autocrine or paracrine factor with powerful immunoregulatory activity. Adenosine signaling downregulates functions of most immune effector cells but enhances expansion and activity of immune cells responsible for suppression of anti-tumor immune responses. Adenosine is critical for limiting potential tissue-destructive effects of activated immune cells. It also facilitates tumor escape from the immune control. This review illustrates the involvement of adenosine and its four receptors, A1R, A2AR, A2BR and A3R, in the complex regulation of cellular and molecular cross talk that contributes to cancer progression. It also considers the potential of therapeutics targeting the adenosinergic pathway for benefiting cancer patients.