IMMU-22 - Reprogramming of microglia/macrophages in glioblastoma improves anti-tumor T cell responses

Friday, November 18, 2022

7:30 PM – 9:30 PM ET

Location: West/Central Hall

Author(s)

VF

Valentina Fermi

Experimental Neurosurgery, Dpt Neurosurgery, University of Heidelberg, Germany
Heidelberg, Germany
RW

Rolf Warta, Baden-Württemberg, Dr.

Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprechts-Karls-University Heidelberg
Heidelberg, Germany
CR

Carmen Rapp

Experimental Neurosurgery, Dpt Neurosurgery, University of Heidelberg, Germany
Heidelberg, United States
PD

Philip Dao Trong, Dr. med.

Experimental Neurosurgery, Dpt Neurosurgery, University of Heidelberg, Germany
Heidelberg, Germany
Gerhard Jungwirth, MD, PhD, MHBA (he/him/his)

Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprechts-Karls-University Heidelberg
Heidelberg, Germany
UA

Unterberg Andreas, MD, Prof.

Department of Neurosurgery, University Hospital Heidelberg
Heidelberg, Germany

Poster Presenter(s)

Christel C. Herold-Mende, PdD

University of Heidelberg
Heidelberg, Germany

Glioma-infiltrating myeloid cells such microglia and macrophages (GAM) are a major component of the immunosuppressive tumor microenvironment in glioblastoma (GBM). Especially their anti-inflammatory M2-like activation state might counteract efficacy of immunotherapeutic interventions by impairing effector T cell infiltration and function. Therefore, we studied the ability of the small molecule inhibitors (SMI) PLX3397, BLZ945, and GW2580 that target the M2-associated colony stimulating factor-1 receptor (CSF1R) to shape GAM phenotype towards a pro-inflammatory M1-like phenotype and how this affects the T cell compartment.Upon treatment of freshly isolated CD11b-sorted GBM patient-derived GAMs (n = 15) a decreased expression of CD163 (M2-like) and an increased expression of HLA-DR (M1-like) as well as an increased nitrite production as an indirect measure for iNOS activation (M1-like) was observed which was most pronounced for BLZ945, and GW2580. Transcriptome analysis of treated vs. untreated GAMs supported a reprogramming towards a pro-inflammatory phenotype. In addition, treatment of GAMs in a GBM patient-derived tumor organoid model confirmed a substantial decrease of CD163+ M2-polarized GAM together with a reduced number of proliferating tumor cells. Finally, treatment of patient-derived GAMs led to an increased T cell transmigration through a dense barrier of autologous tumor-derived endothelial cells and increased the ability of T cells to kill autologous tumor cells. Our results support CSF1R blockade is able to reduce the immunosuppressive and pro-tumorigenic functions of GAM substantially and thereby could enhance the effectiveness of T cell-based immunotherapy.