Artikel
Personalised treatment option in translational neuro-oncology – JAK/STAT-inhibition reverses myeloid cell-induced anti-tumour-immunity in T cells
Personalisierter Therapieansatz in der Translationalen Neuroonkologie – JAK/STAT-Hemmung kehrt die durch myeloide Zellen-induzierte Antitumor-Immunität in T-Zellen um
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Veröffentlicht: | 4. Juni 2021 |
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Gliederung
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Objective: Recently, we demonstrated that JAK/STAT-inhibition leads to the conversion of the immune environment of glioblastoma from “cold” to “hot”. Here, we explored transcriptional programs of tumor-associated T cells and potential targets to reverse the major group of dysfunctional T cells using a human neocortical slice model in addition to computational models.
Methods: We acquired single-cell sequencing of 50k CD45+ cells (8 patients) and inferred transcriptional programs and fate decisions using RNA-velocity. A novel algorithm (“Nearest functionally connected neighbor”, NFCN) was used to predict neighboring cells, validated by spatial transcriptomics and immunohistochemistry. A human neocortical glioblastoma slice model with autografted T cells was used to test a JAK/STAT inhibitor, further used in neoadjuvant treatment of a single patient.
Results: We observed that most T cells in the GBM microenvironment showed either increased expression of exhaustion markers or hypoxia related non-functional signatures. Pseudo-time analysis revealed increased Interleukin 10 (IL10) response during the transformation of T cells from the effector to the exhausted state. Using our novel NFCN-algorithm, we identified a subset of myeloid cells marked by increased HMOX1 expression (in STAT/HMOX axis) to be responsible for release of IL10. We validated our computational findings by using human neocortical glioblastoma slice model with autografted T cells, confirming that IL10R-inhibition or myeloid cell depletion rescued T cells from exhaustion. In order to target the STAT/HMOX axis, we used a JAK/STAT inhibitor in our GBM model, which showed a significant reduction of IL10 release and consecutive activation of T cells. In a clinical setting, a single patient treated with a JAK/STAT-inhibitor showed clear activation of T cells, validated by means of scRNA sequencing and immunostainings.
Conclusion: Our findings suggest that targeting the myeloid cell environment of GBM provides an opportunity to convert a “cold” into “hot” immune environment which might be helpful to improve all T cell-based therapies in the future.