A combined immunopeptidomics, proteomics, and cell surface proteomics approach to identify immunotherapy targets for diffuse intrinsic pontine glioma

Kirti Pandey; Stacie S Wang; Nicole A Mifsud; Pouya Faridi; Alexander J Davenport; Andrew I Webb; Jarrod J Sandow; Rochelle Ayala; Michelle Monje; Ryan S Cross; Sri H Ramarathinam; Misty R Jenkins; Anthony W Purcell

doi:10.3389/fonc.2023.1192448

A combined immunopeptidomics, proteomics, and cell surface proteomics approach to identify immunotherapy targets for diffuse intrinsic pontine glioma

Front Oncol. 2023 Aug 11:13:1192448. doi: 10.3389/fonc.2023.1192448. eCollection 2023.

Authors

Kirti Pandey¹, Stacie S Wang^{2

3}, Nicole A Mifsud¹, Pouya Faridi^{4

5

6

7

8}, Alexander J Davenport², Andrew I Webb⁹, Jarrod J Sandow⁹, Rochelle Ayala¹, Michelle Monje¹⁰, Ryan S Cross², Sri H Ramarathinam¹, Misty R Jenkins^{2

11

12}, Anthony W Purcell¹

Affiliations

¹ Department of Biochemistry and Molecular Biology and Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
² Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
³ Children's Cancer Centre, Royal Children's Hospital, Parkville, VIC, Australia.
⁴ Monash Proteomics and Metabolomics Facility, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
⁵ School of Clinical Sciences, Department of Medicine, Monash University, Clayton, VIC, Australia.
⁶ Department of Medicine, Sub-Faculty of Clinical and Molecular Medicine, Faculty of Medicine, Nursing & Health Sciences, Monash University, Clayton, VIC, Australia.
⁷ Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia.
⁸ Department of Molecular and Translational Medicine, School of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
⁹ Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
¹⁰ Department of Neurology and Neurological Sciences and Howard Hughes Medical Institute, Stanford University, Stanford, CA, United States.
¹¹ The Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
¹² LaTrobe Institute for Molecular Science, LaTrobe University, Bundoora, VIC, Australia.

Abstract

Introduction: Diffuse intrinsic pontine glioma (DIPG), recently reclassified as a subtype of diffuse midline glioma, is a highly aggressive brainstem tumor affecting children and young adults, with no cure and a median survival of only 9 months. Conventional treatments are ineffective, highlighting the need for alternative therapeutic strategies such as cellular immunotherapy. However, identifying unique and tumor-specific cell surface antigens to target with chimeric antigen receptor (CAR) or T-cell receptor (TCR) therapies is challenging.

Methods: In this study, a multi-omics approach was used to interrogate patient-derived DIPG cell lines and to identify potential targets for immunotherapy.

Results: Through immunopeptidomics, a range of targetable peptide antigens from cancer testis and tumor-associated antigens as well as peptides derived from human endogenous retroviral elements were identified. Proteomics analysis also revealed upregulation of potential drug targets and cell surface proteins such as Cluster of differentiation 27 (CD276) B7 homolog 3 protein (B7H3), Interleukin 13 alpha receptor 2 (IL-13Rα2), Human Epidermal Growth Factor Receptor 3 (HER2), Ephrin Type-A Receptor 2 (EphA2), and Ephrin Type-A Receptor 3 (EphA3).

Discussion: The results of this study provide a valuable resource for the scientific community to accelerate immunotherapeutic approaches for DIPG. Identifying potential targets for CAR and TCR therapies could open up new avenues for treating this devastating disease.

Keywords: DIPG; HLA; immunopeptidomics; paediatric brain cancer; proteomics; surfaceome.

Grants and funding

This project was funded by a Cancer Council of Australia grant 1164657 (to AP and MJ), an Australian National Health and Medical Research Council (NHMRC) Project Grant 1165490 (to AP), and the Mark Hughes Foundation (to AP and PF). The authors would like to acknowledge the support of the Walter and Eliza Hall Institute of Medical Research, Dawes Foundation, and the Brain Cancer Centre. AP is supported by a NHMRC Principal Research Fellowship (1137739). MJ is supported by a NHMRC Investigator Grant (1172858) and NHMRC Synergy Grant (2010849). SW is supported by the Isabella and Marcus Foundation, Matthew Rathbone Clinical Research Fellowship, and My Room Children’s Cancer Charity. RC was supported by Cure Brain Cancer Foundation Early Career Fellowship (2018). PF was supported by the Victorian Department of Health and Human Services acting through the Victorian Cancer Agency. PF was supported by grant 2001870 awarded through the 2020 Priority-driven Collaborative Cancer Research Scheme and co-funded by Cancer Australia and the Australian Lions Childhood Cancer Research Foundation and My Room Children’s Cancer Charity Ltd.