575 Epigenetic modulation by KDM6B in myeloid cells regulates glioblastoma immune checkpoint therapy outcomes
Bibliographic record
Abstract
Background Glioblastoma (GBM), a disease with a grim overall prognosis, exhibits inherent resistance to immune checkpoint therapy (ICT). GBM tumors notably contain immune-suppressive myeloid cell subsets, which contribute to this resistance. The potential to enhance ICT response by targeting specific epigenetic pathways to reprogram these immune-suppressive myeloid cells into an immune-stimulatory phenotype remains largely unexplored. Our objective was to identify key epigenetic factors that regulate immune-suppressive pathways in myeloid cells and to target these factors to overcome myeloid cell-mediated resistance to ICT in GBM. Methods To identify epigenetic factors in intratumoral myeloid cell subsets, we performed scRNA-seq and spatial transcriptomic analysis (Visium) on CD45+ immune cells from GBM patient samples (MD Anderson IRB-approved protocol PA13-029). We investigated the impact of myeloid-specific Kdm6b deletion on the GBM tumor immune microenvironment using scRNA-seq on GBM tumors from control and LysMcreKDM6Bfl/fl mice carrying the Kdm6b deletion in myeloid cells. For mechanistic insights, we conducted scATAC-seq and CHIPseq on CD45+ cells from tumors and bone marrow derived macrophages of mice. To determine the translational relevance of our findings from the genetic model, we compared murine GBM tumor growth and the tumor immune microenvironment in the presence and absence of a pharmacological inhibitor of KDM6B (GSK-J4). Results Single-cell and spatial transcriptomic analyses of human GBM tumors revealed that intratumoral immune-suppressive myeloid cell subsets highly express the epigenetic enzyme histone 3 lysine 27 demethylase (KDM6B). Significantly, the deletion of Kdm6b specifically in myeloid cells led to reduced tumor burden and improved survival in preclinical GBM models. Mechanistic studies showed that Kdm6b-deficient myeloid cells had altered epigenetic and transcriptomic profiles, with an increased interferon response, enhanced phagocytic ability, and improved antigen presentation. Additionally, pharmacological inhibition of KDM6B in a murine GBM model replicated the genetic model’s functional phenotype and improved survival following anti-PD1 therapy. Conclusions This study identified KDM6B as a key epigenetic regulator of myeloid cell phenotype and function, underscoring its potential as a therapeutic target to improve responses to anti-PD1 therapy. Acknowledgements This research is supported by the MD Anderson Physician Scientist Award, Khalifa Physician Scientist Award, Andrew Sabin Family Foundation Fellows Award and Clinic and Laboratory Integration Program Award awarded to Sangeeta Goswami. Ethics Approval MD Anderson IRB-approved protocol PA13-029.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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; a candidate call from one source (direct Gemma or distilled Codex), 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".