Tmic-06. Antagonism of Drd2 Using Onc201 Increased Expression of Antigen Presentation Pathway Proteins in Diffuse Midline Glioma, Recruiting Tumor Infiltrating Lymphocytes in Vivo
Year: 2022
Type: conference-abstract
Abstract: Diffuse midline glioma (DMG) is a high-grade glioma with a median overall survival of 9-11 months. Radiotherapy is the only recognized treatment. The DMG tumor microenvironment (TME) contains few, if any, tumor infiltrating lymphocytes (TILs) or inflammatory cytokines, thus is distinctive of an ‘immunologically cold’ tumor/TME.1 DMG lack the expression of immunosuppressive immune checkpoint proteins, likely explaining the failure of immune checkpoint inhibitors (ICI) tested under clinical trials for DMG patients, and suggestive of an alternative mechanism underpinning the cold TME. 1 Glioblastomas also harbor a cold TME, which can be somewhat explained by T cell lymphopenia, influenced by the sequestration of T cells in the bone marrow (through Beta-arrestin-induced internalization of Sphingosine-1-phosphate receptor 1 [S1PR1]). 2 Dopaminergic activation of Beta-arrestin and hence S1PR1 internalization, is potentially regulated through dopaminergic peripheral nerves in primary and secondary lymphoid organs, regulated by the Dopamine receptor D2 (DRD2), that is highly expressed on T cells. ONC201 is a potent DRD2 antagonist, currently in phase I-III clinical trials for DMG patients, alone and in combination with radiotherapy and the PI3K/AKT inhibitor paxalisib (NCT05009992). Proteomic profiling of DMG patient-derived cells +/-ONC201 showed increased expression of several antigen presenting pathway proteins, including Beta-2-microglobulin (B2M) and HLA class I histocompatibility antigen, A alpha chain (HLA-A). This was confirmed in vivo using SU-DIPG-VI patient-derived xenograft mouse model tissues +/-ONC201 alone, and together with paxalisib. Excitingly, this combination (given orally) promoted the recruitment of TILs to the tumor, revealing novel immunomodulatory effects. In vivo, ONC201 promoted the expression of EMILIN-3, a TGF-β antagonist that is known to inhibit HLA-A/B2M expression, possibly explaining the increased MHC-I activity. This study uncovers a novel link between treatment of DMG with ONC201 and paxalisib and the role dopaminergic peripheral nerves signaling may play on the sequestration of T cells within lymphoid organs and lymphopenia.
Source: Neuro-Oncology
Authors: Mika Persson, Evangeline Jackson, Ryan Duchatel, Liesl Bramberger, Holly McEwen, Padraic Kearney, Izac Findlay, Alicia Douglas, Birgit Kobbe, Raimund Wagener, Martin Larsen, Pouya Faridi, Jeff Holst, Jemma Mayall, Craig Gedye, Hubert Hondermarck, Jay Horvat, Brett Nixon, Rodrigo Cartaxo, Carl Koschmann, Fatima Valdes-Mora, David Gallego Ortega, Javad Nazarian, Marta M Alonso, Esther Hulleman, Jasper Van der Lugt, Nicholas Vitanza, Sabine Mueller, Matthew Dun
Institutions: University of Newcastle Australia, Monash University, University of Cologne, University of Southern Denmark, UNSW Sydney, Hunter Medical Research Institute, Calvary Mater Newcastle Hospital, University of Michigan, Michigan Medicine, University of Technology Sydney, University Children's Hospital Zurich, Clinica Universidad de Navarra, Princess Máxima Center, Seattle Children's Research Institute, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4308977965