Dysfunctional dendritic cells limit antigen-specific T cell response in glioma

Abstract

Background Dendritic cells (DC), the most potent professional antigen presenting cells capable of effective cross-presentation, have been demonstrated to license T helper cells to induce antitumor immunity in solid tumors. Specific DC subtypes are recruited to the injured brain by microglial chemokines, locally adapting to distinct transcriptional profiles. In isocitrate dehydrogenase (IDH) type 1 mutant gliomas, monocyte-derived macrophages have recently been shown to display an attenuated intratumoral antigen presentation capacity as consequence of the local accumulation of the oncometabolite R-2-hydroxyglutarate. The functionality and the contribution of DC to the IDH-mutant tumor microenvironment (TME) remains unclear. Methods Frequencies and intratumoral phenotypes of human DC in IDH-wildtype (IDHwt) and -mutant high-grade gliomas are comparatively assessed by transcriptomic and proteomic profiling. DC functionality is investigated in experimental murine glioblastomas expressing the model antigen ovalbumin. Single-cell sequencing-based pseudotime analyses and spectral flow cytometric analyses are used to profile DC states longitudinally. Results DC are present in primary and recurrent high-grade gliomas and interact with other immune cell types within the TME. In murine glioblastomas, we find an IDH-status-associated major histocompatibility class I-restricted cross-presentation of tumor antigens by DC specifically in the tumor but not in meninges or secondary lymphoid organs of tumor-bearing animals. In single-cell sequencing-based pseudotime and longitudinal spectral flow cytometric analyses, we demonstrate an IDH-status-dependent differential, exclusively microenvironmental education of DC. Conclusions Glioma-associated DCs are relevantly abundant in human IDHwt and mutant tumors. Glioma IDH mutations result in specifically educated, dysfunctional DCs via paracrine reprogramming of infiltrating monocytes, providing the basis for combinatorial immunotherapy concepts against IDH mutant gliomas.

Deciphering diffuse glioma immune microenvironment as a key to improving immunotherapy results

“…We have focused on the main players of TME, with a focus on TAMMs and T-cells. However, more research is unravelling that other immune cells may have a relevant role in this complexity, including neutrophils [72], dendritic cells [73] and B-cells [74–75]. It is also becoming clear that the plasticity of TME is modelled by treatment (radiotherapy, chemotherapy, targeted therapies and immunotherapy) and by metabolic requirements, calling for rapid adjustments that can be provided by epigenetic reshaping [49 ▪▪ ].…”

Dendritic cell vaccines improve the glioma microenvironment: Influence, challenges, and future directions

“…In the glioma patients with isocitrate dehydrogenase (IDH) mutation, β‐ketoglutarate is converted to D‐2‐HG and the latter appears to drive extensive epigenetic changes that alter cell differentiation and possibly promote tumorigenesis 39 . D‐2‐HG can lead to specifically educated, dysfunctional DCs by reprogramming of the lipopolysaccharide (LPS)‐induced metabolism, 38,40 promoting oxidative phosphorylation, inhibiting glycolysis, and inhibiting p34/IL‐12A and p35/IL‐12B expression, 41 thus reducing IL‐12 and promoting immune escape from tumor cells 42 . Glioma cells can induce Nrf overexpression in the DCs, which in turn leads to the inhibition of DC maturation and reduced effector T cell activation 43 .…”

Clinical and Translational Advances in Glioma Immunotherapy

“…As DC products need to be manufactured under GMP conditions and applied vitally, production costs are higher compared to RNA or peptide vaccines. However, DC activation, which is naturally suppressed in cancer patients [41,42] but important for vaccine-induced T cell priming, can be robustly achieved in vitro.…”