SYST-26 INVESTIGATING THE FUNCTIONAL ROLE OF GPNMB IN GLIOBLASTOMA AND THE TUMOR IMMUNE MICROENVIRONMENT AND ITS TARGETED ELIMINATION USING CAR-T CELLS
Bibliographic record
Abstract
Abstract 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<0.001) and prolonged survival times in all mouse models (P<0.01). GPNMB knockout clones displayed downregulation of hallmark signaling pathways of GBM such as PDGFR, TGF-beta, Integrins and Stats, and decreased innate/adaptive immune activation. CAR-T cytotoxicity and activation was observed in vitro and in vivo resulting in decreased tumor burden (P<0.001) and increased survival times (P<0.001). CONCLUSIONS We show GPNMB influences tumor-intrinsic biology of GBM and is also active in macrophages in the recurrent GBM immune microenvironment. By targeting GPNMB alongside CD133, combinatorial therapeutic regimens could target both the cancer stem cell hierarchy and its supportive niche. Administration of both CAR-T cell therapies to humanized mice engrafted with patient-derived GBMs is underway.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".