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.
Highlights
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
To computationally explore the “connected” cells driving this transformation, we introduce an in silico approach termed “Nearest Functionally Connected Neighbor (NFCN)”, which identified a subset of myeloid cells, marked by CD163 and Heme Oxygenase 1 (HMOX1) expression
Using a human neocortical GBM model coupled with patient-derived T cells to simulate the lymphoid compartment, we validated the role of HMOX1+ myeloid cells as key drivers for the immunosuppressive microenvironment found in glioblastoma
Summary
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. 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 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. Immunotherapies such as PDL1/PD1 checkpoint blockade[17] or peptide vaccination[18], that have led to remarkable improvement in therapeutic outcome for several types of cancer, has failed to demonstrate its effectiveness in patients suffering from glioblastoma To address this sparsity of knowledge with respect to the lymphoid cell population in glioblastoma, we performed transcriptional profiling using scRNA-sequencing, mapping potential cellular interactions and/or cytokine responses that could lead to dysfunctional and/or exhausted T cells. Our findings open perspectives to target the tumor microenvironment and to improve immunotherapy response in glioblastoma
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