| Title: |
SYST-26 INVESTIGATING THE FUNCTIONAL ROLE OF GPNMB IN GLIOBLASTOMA AND THE TUMOR IMMUNE MICROENVIRONMENT AND ITS TARGETED ELIMINATION USING CAR-T CELLS |
| Authors: |
Savage, Neil; Zemp, Franz; Mikolajewicz, Nicholas; Han, Hong; Venugopal, Chitra; Tatari, Nazanin; Chokshi, Chirayu; Kislinger, Thomas; Mahoney, Douglas; Moffat, Jason; Singh, Sheila |
| Source: |
Neuro-Oncology Advances ; volume 5, issue Supplement_3, page iii33-iii33 ; ISSN 2632-2498 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2023 |
| Description: |
INTRODUCTION Glycoprotein nonmetastatic melanoma protein B (GPNMB) is active in the extracellular matrix of glioblastoma and presents a promising immunotherapy target for both tumor cells and immunosuppressive macrophages. METHODS Immunohistochemistry was performed on patient derived xenograft (PDX) brains and tissue samples of 16 patient-matched primary/recurrent GBMs and 23 normal organ tissues. Whole cell proteomics was performed on 43 matched primary/recurrent GBM samples. CRISPR/Cas9 was used to eliminate expression in GBM lines and proliferation and mouse survival times measured. GPNMB knockout clones generated in GL261 were engrafted in immunocompetent mice to examine single cell transcriptomes using sciRNA sequencing at endpoint. A second-generation CAR-T was developed to target GPNMB-expressing populations, and efficacy was interrogated using in vitro assays and GBM PDX models. RESULTS GPNMB was absent in most normal tissues but detected in residual PDX tumors treated orthotopically with CD133 CAR-Ts. Tissue microarrays and whole cell proteomics showed GPNMB upregulation in recurrent GBMs compared to primary (p=0.0349 vs. p=0.0033) while absent in normal tissues. Single cell sequencing data of patient GBMs revealed GPNMB was also highly expressed in tumor-associated macrophages. Eliminating GPNMB in GBM cell lines decreased proliferation (P |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/noajnl/vdad070.128 |
| Availability: |
https://doi.org/10.1093/noajnl/vdad070.128; https://academic.oup.com/noa/article-pdf/5/Supplement_3/iii33/51037795/vdad070.128.pdf |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.C6B027D3 |
| Database: |
BASE |