TMIC-06 - Antagonism of DRD2 using ONC201 increased expression of antigen presentation pathway proteins in diffuse midline glioma, recruiting tumor infiltrating lymphocytes in vivo

Friday, November 18, 2022

7:30 PM – 9:30 PM ET

Location: West/Central Hall

Author(s)

MP

Mika L. Persson

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
EJ

Evangeline R. Jackson

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
RD

Ryan J. Duchatel

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
LB

Liesl Bramberger

Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia
Melbourne, Australia
HM

Holly McEwen

Cancer Signalling Research Group, School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
PK

Padraic S. Kearney

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
IF

Izac J. Findlay

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
AD

Alicia M. Douglas

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
BK

Birgit Kobbe

Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
Cologne, Germany
RW

Raimund Wagener

Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
Cologne, Germany
ML

Martin R. Larsen

Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark
Odense M, Denmark
PF

Pouya Faridi

Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia
Melbourne, Australia
JH

Jeff Holst

Translational Cancer Metabolism Laboratory, School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia
Sydney, Australia
JM

Jemma Mayall

Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW, Australia
Newcastle, Australia
Craig Gedye, MBChB, FRACP, PhD

Department of Medical Oncology, Calvary Mater Hospital, Waratah, NSW, Australia
Newcastle, Australia
HH

Hubert Hondermarck

Cancer Neurobiology Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Newcastle, Australia
JH

Jay Horvat

Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW, Australia
Newcastle, Australia
BN

Brett Nixon

Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
New Lambton Heights, Australia
RC

Rodrigo Cartaxo, PhD

Department of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA
Ann Arbor, United States
Carl J. Koschmann, MD

Department of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA
Ann Arbor, United States
FV

Fatima Valdes-Mora

Cancer Epigenetics Biology and Therapeutics, Precision Medicine Theme, Children’s Cancer Institute, Sydney, NSW, Australia
Sydney, Australia
DG

David Gallego Ortega

University of Technology Sydney, Centre for Single Cell Technology, Sydney, New South Wales, Australia
Sydney, Australia
Javad Nazarian, PhD, MS

Department of Oncology, Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
Zurich, Switzerland
Marta M. Alonso, PhD (she/her/hers)

Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain and Program of Solid Tumors, Center for the Applied Medical Research
Pamplona, Spain
EH

Esther Hulleman

Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
Utrecht, Netherlands
JV

Jasper Van der Lugt, MD; PhD

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Utrecht, Netherlands
Nicholas A. Vitanza, MD

Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute, Seattle, WA, USA
Seattle, United States
Sabine Mueller, MD, PhD, MAS (she/her/hers)

UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
San Francisco, United States

Poster Presenter(s)

Matthew D. Dun, Ph.D (he/him/his)

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia

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.