Perioperative corticosteroid treatment impairs tumor-infiltrating dendritic cells in patients with newly diagnosed adult-type diffuse gliomas

Abstract

IntroductionAdult-type diffuse gliomas are malignant primary brain tumors characterized by very poor prognosis. Dendritic cells (DCs) are key in priming antitumor effector functions in cancer, but their role in gliomas remains poorly understood.MethodsIn this study, we characterized tumor-infiltrating DCs (TIDCs) in adult patients with newly diagnosed diffuse gliomas by using multi-parametric flow cytometry and single-cell RNA sequencing.ResultsWe demonstrated that different subsets of DCs are present in the glioma microenvironment, whereas they are absent in cancer-free brain parenchyma. The largest cluster of TIDCs was characterized by a transcriptomic profile suggestive of severe functional impairment. Patients undergoing perioperative corticosteroid treatment showed a significant reduction of conventional DC1s, the DC subset with key functions in antitumor immunity. They also showed phenotypic and transcriptional evidence of a more severe functional impairment of TIDCs.DiscussionOverall, the results of this study indicate that functionally impaired DCs are recruited in the glioma microenvironment. They are severely affected by dexamethasone administration, suggesting that the detrimental effects of corticosteroids on DCs may represent one of the mechanisms contributing to the already reported negative prognostic impact of steroids on glioma patient survival.

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“…In addition to corticosteroid-dependent reduction of MHCII and CD40 on DC, they also identified a heterogeneous population of DC within patient HGG samples, including cDC1, cDC2, and moDC. cDC1 comprised the smallest portion, and significant levels of pDC were only detected in one out of a total of five untreated patients [46]. In a single cell RNA-sequencing study, Antunes et al confirmed the reported DC heterogeneity in humans and extended these findings in a murine model of GBM.…”

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“…However, considering that antigen presentation occurs at this CNS immune interface during neuroinflammation [39], we speculate meninges may also harbor the CI cycle 1 3 anti-tumoral T-cell activation and a weaker immunological response in GBM [20]. Notably, although DCs are negligible in healthy brain parenchyma [21], almost all subsets of DCs can be observed in the core lesions of gliomas [22]. Thus, released tumor antigens can also captured by DCs infiltrated in GBM [23].…”

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“…However, other research groups found no significant difference in neutrophil counts in patients receiving or not receiving steroid therapy ( 108 ) or revealed only a weak correlation between the dexamethasone dose and NLR ( 109 ). Finally, perioperative corticosteroid treatment impaired tumor-infiltrating dendritic cells in patients with newly diagnosed gliomas ( 110 ). Altogether, in accordance with in vitro and ex vivo studies, dexamethasone (without radiochemotherapy) adversely affects the immune system of patients with cancer.…”