gms | German Medical Science

73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

29.05. - 01.06.2022, Köln

Article

Send article

Personalised therapeutic approach in translational neuro-oncology – JAK/STAT inhibition reverses the anti-tumour immunity induced by myeloid cells in T cells

Personalisierter Therapieansatz in der Translationalen Neuroonkologie: JAK/STAT-Hemmung kehrt die durch myeloide Zellen-induzierte Antitumor-Immunität in T-Zellen um

Meeting Abstract

Search Medline for

  • presenting/speaker Vidhya Madapusi Ravi - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Neuroelectronic Systems, Freiburg i. Br., Deutschland
  • Nicolas Neidert - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland
  • Kevin Joseph - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland
  • Jürgen Beck - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland
  • Oliver Schnell - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland
  • Dieter Henrik Heiland - Universitätsklinikum Freiburg, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Translational NeuroOncology Research Group, Freiburg i. Br., Deutschland; Universitätsklinikum Freiburg, Klinik für Neurochirurgie, Freiburg i. Br., Deutschland

Deutsche Gesellschaft für Neurochirurgie. 73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie. Köln, 29.05.-01.06.2022. Düsseldorf: German Medical Science GMS Publishing House; 2022. DocV079

doi: 10.3205/22dgnc082, urn:nbn:de:0183-22dgnc0826

Published: May 25, 2022

© 2022 Ravi et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

Text

Objective: Recently, we demonstrated that JAK/STAT-inhibition causes a “cold” into “hot” conversion of the immune environment of glioblastoma. 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 and computational models.

Methods: We acquired single-cell sequencing of 50k CD45(+) cells (8 patients) and inferred transcriptional programs and fate decisions in T cells, using RNA-velocity and our computational pipeline (SPATA). A novel algorithm (“Nearest functionally connected neighbor”, NFCN) was used to predict neighboring cells, which was validated in spatial transcriptomic datasets and immunohistochemistry staining. We validated our findings using a human neocortical glioblastoma slice model with autografted T cells. The promising candidate, a JAK/STAT inhibitor, was tested in neoadjuvant treatment in a single patient. The treatment effect was validated by single-cell RNA-sequencing in the post treatment tissue.

Results: Our computational analysis identified a subset of myeloid cells marked by HMOX1+ expression (in STAT/HMOX axis) to be responsible for release of IL10 which further leads to T cell exhaustion. And, using human neocortical glioblastoma slice model with autografted T cells, we were able to prove evidently that IL10R-inhibition or myeloid cell depletion rescued the T cell exhaustion. In order to target the STAT/HMOX axis we used a JAK/STAT inhibitor in our slice model which showed a significant reduction (p<0.001) of IL10 release and consecutive activation of T cells. Clinically, one single patient treated with a JAK/STAT-inhibitor in a neoadjuvant setting, 4 weeks prior to the recurrent GBM surgery, showed a clear significant activation (p<0.005) of T cells using 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 T cell based therapies in the future.