87P Macrophage ontogeny underlies functional programs and drives brain tumor progression
Bibliographic record
Abstract
Glioblastoma is the most common and aggressive primary brain cancer with an overall survival of 15 months despite aggressive cytotoxic treatments. Therefore, identifying new therapeutic targets within the tumor microenvironment (TME) is critical for improving patient outcomes. In glioblastoma, macrophages make up to 30% of the bulk tumor, which include both yolk-sac derived tissue-resident microglia and monocyte-derived macrophages (MDMs) that are recruited from the bone marrow during inflammation. During hematopoiesis, MDMs can arise from granulocyte-monocyte progenitors (GMPs) or monocyte-dendritic cell progenitors (MDPs), which give rise to neutrophil-like or dendritic cell-like lineages, respectively. Although MDMs as a whole are often considered tumor-promoting, the functional role of specific MDM ontogenies is not known. Our recent study identified a subset of MPO+ MDMs associated with better overall survival, enhanced cytotoxic function, and gene expression suggestive of a GMP origin. Therefore, the aim of this study is to characterize the role of MDM ontogeny in brain tumor progression. Using a combination of RNA-sequencing, in vitro functional assays and in vivo fate-mapping tools, we assessed the functional role of macrophage ontogeny in glioblastoma models. Additionally, we adoptively transferred monocytes cultured ex vivo from distinct developmental origins to trace their recruitment to tumors and assess the subsequent impact on tumor growth. Interestingly, macrophage ontogeny was associated with differences in MHC I-mediated and MHC II-mediated antigen presentation as well as unique profile of cytokines and chemokines, including MPO. Additionally, we found differences in phagocytosis towards glioma cells and upregulation of different inflammatory pathways. Importantly, adoptive transfer of monocytes of distinct ontogenies had opposing effects on brain tumor progression and resulted in significant changes to the TME and peripheral immune system. Our findings shed light on the developmental origins of brain tumor MDMs and their putative regulatory impact in the TME.
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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 | 0.000 | 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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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; both teacher heads agree on what is shown here.
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".