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

The tumour microenvironment counteracts immune therapy in Glioblastomas. Authors show here, using spatially resolved and single cell transcriptomics, that dysfunctional T cells are induced by a myeloid cell subset via Interleukin-10 signalling, and inhibition of the downstream JAK/STAT pathway might restore glioblastoma immune therapy responsiveness. 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.

Automated summary

The study demonstrates that a subset of myeloid cells in Glioblastomas induce dysfunctional T cells through Interleukin-10 signaling, and inhibiting downstream JAK/STAT pathway could restore the responsiveness of immune therapy. The findings are validated using in vitro and in vivo models, providing further evidence of Interleukin-10 release being a driving force of tumor immune escape. Integrative modeling of single cell and spatial transcriptomics data proves to be a valuable tool for studying the tumor immune microenvironment and may contribute to the development of successful immunotherapies.