T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10

Abstract

Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the anti-tumor immune response. Here we show, by applying an in-silico multidimensional model integrating spatially resolved and single-cell gene expression data of 45,615 immune cells from 12 tumor samples, that a subset of Interleukin-10-releasing HMOX1+ myeloid cells, spatially localizing to mesenchymal-like tumor regions, drive T-cell exhaustion and thus contribute to the immunosuppressive tumor microenvironment. These findings are validated using a human ex-vivo neocortical glioblastoma model inoculated with patient derived peripheral T-cells to simulate the immune compartment. This model recapitulates the dysfunctional transformation of tumor infiltrating T-cells. Inhibition of the JAK/STAT pathway rescues T-cell functionality both in our model and in-vivo, providing further evidence of IL-10 release being an important driving force of tumor immune escape. Our results thus show that integrative modelling of single cell and spatial transcriptomics data is a valuable tool to interrogate the tumor immune microenvironment and might contribute to the development of successful immunotherapies.

Myeloid Cell Classification and Therapeutic Opportunities Within the Glioblastoma Tumor Microenvironment in the Single Cell-Omics Era

“…With the continuing refinement of spatial multiplex imaging technologies, detailed characterizations of the immune proteome within the TME have become possible. Using these techniques, one study found that myeloid cells localized to mesenchymal-like regions of GBM drive T cell exhaustion via IL-10 release, and that this T cell function was rescued with Janus kinase-signal transducer and activator of transcription (JAK/STAT) inhibition, providing a potential therapeutic opportunity ( 57 ). These techniques are allowing for the discovery of wider and more heterogeneous populations of immune cells with newly identified, previously unexploited cell phenotypes with distinct functions that influence tumor biology.…”

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors

“…While previous therapeutic strategies have focused on the depletion of these cell types, there is now increasing efforts in reprogramming immunosuppressive microenvironments (Coniglio et al, 2012; Pyonteck et al, 2013; Quail and Joyce, 2017). These reprogramming strategies have largely focused on skewing the phenotype of bbm from an immunosuppressive M2-like to a proinflammatory M1-like phenotype assuming that immunosuppression by bbm is driven by soluble factors such as IL10 or TGFb (Poon et al, 2017; Ravi et al, 2022). MHCII expression is considered a marker of proinflammatory M1-like bbm but the functional relevance of MHCII has remained ill-understood.…”

The Dynamics of Tumor-Infiltrating Myeloid Cell Activation and the Cytokine Expression Profile in a Glioma Resection Site during the Post-Surgical Period in Mice

“…Additionally, IL10, which was found in our study to be upregulated in regrown tumors compared with primary implanted tumors, was shown to promote glioma cell growth and invasion [ 32 , 33 ] Moreover, IL-10 was shown to suppress proliferation, cytokine production, and migration of effector T-cells, driving T-cell exhaustion and thus creating an immunosuppressing environment in the tumor [ 34 , 35 ]. Increased expression of IL-10 in GBM patients was correlated with brief survival [ 36 ].…”