Contributor:

Kamińska-Kaczmarek, Bożena (1961– ) : Supervisor ; Ellert-Miklaszewska, Aleksandra (1974- ) : Assistant supervisor

Publisher:

Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN

Place of publishing:

Warszawa

Description:

117 pages : illustrations ; 30 cm ; Bibliography ; Summary in English

Degree name:

PhD in Biological Sciences

Degree discipline :

Biological Sciences

Degree grantor:

Nencki Institute of Experimental Biology PAS ; degree obtained: 10.10.2025

Type of object:

Thesis

Abstract:

Malignant glioma with a wild-type IDH1/2 (glioblastoma, GBM, wt-IDH1/2) is the most common and aggressive brain tumor in adults. Current therapies for GBM are not effective and most tumors recur within months. The development of tumor is associated with deficits of the host's antitumor defense. The goal of immunotherapy is to restore the anti-tumor immune response, and immune checkpoint inhibitors offer the potential to completely eradicate cancer. However, GBM patients respond poorly to immunotherapies because the tumors are characterized by meager infiltration of functional T lymphocytes and NK cells. Myeloid cells accumulating in the GBM (including resident microglia and peripheral macrophages, collectively known as glioma associated myeloid cells - GAMs) are reprogrammed to support the tumor and exert an immunosuppressive effect in the tumor microenvironment. One of the factors responsible for these processes is the SPP1 (secreted phosphoprotein 1) protein secreted by glioma. The aim of this study was to develop new strategies to reactivate the anti-tumor response in malignant gliomas and to sensitize the tumor to the action of anti-PD-1 antibodies. These strategies involve reprogramming the phenotype of GAMs. Using a syngeneic model of glioma in mice, two therapeutic approaches were employed: i) blocking the activity of arginase 1 (Arg1) using OAT-1746 - a new, potent and selective, small- molecule inhibitor of the enzyme, and ii) preventing the action of Spp1 using a short peptide that blocks the Spp1-integrin interaction. Activation of Arg1 in GAMs leads to depletion of L-arginine, a nutrient required for T and NK cell proliferation, while activation of integrin receptors by Spp1 contributes to the induction of the pro-tumor phenotype of GAMs. The effects of immunomodulators on GL261 glioma growth in vivo were assessed using magnetic resonance imaging or the Xtreme intravital imaging. The glioma microenvironment following immunomodulator administration was characterized using multiparametric flow cytometry analysis and transcriptomic profiling (RNAseq) of isolated CD11b+ cells. The antitumor efficacy of immunomodulators administered alone or in combination with PD-1 blockade was assessed. Oral administration of OAT-1746 had no effect on the immune cell composition in the glioma microenvironment, but induced transcriptomic changes in CD11b+ cells immunosorted from the brains of inhibitor-treated mice. Administration of OAT-1746 with anti-PD-1 antibody reduced tumor growth. Intratumorally delivered RGD peptide effectively blocked the reprogramming of GAMs towards a glioma-supporting phenotype, but did not affect tumor size. The use of the RGD peptide in combination with the anti-PD-1 antibody changed the composition and functionality of immune cells and enhanced pro-inflammatory responses, which led to a reduction in tumor size. The presented results indicate that the tested immunomodulators change the glioma microenvironment, enable the influx of effector lymphocytes and support the action of immune checkpoint inhibitor immunotherapy.

Detailed Resource Type:

PhD Dissertations

Resource Identifier:

oai:rcin.org.pl:246436

Source:

IBD PAN, call no. 20809

Language:

pol

Language of abstract:

eng

Rights:

Rights Reserved - Free Access

Terms of use:

Copyright-protected material. May be used within the limits of statutory user freedoms

Copyright holder:

Publication made available with the written permission of the author

Digitizing institution:

Nencki Institute of Experimental Biology of the Polish Academy of Sciences

Original in:

Library of the Nencki Institute of Experimental Biology PAS

Access:

Open