CDK4/6 inhibition reprograms the breast cancer immunopeptidome via Rb-dependent chromatin and transcriptomic remodeling
Bibliographic record
Abstract
The cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are standard-of-care therapies for metastatic hormone receptor-positive (HR+) breast cancer, yet their immunomodulatory effects remain underexplored. Here, we demonstrate that CDK4/6 inhibition with Abemaciclib reprograms the tumor antigen landscape by increasing major histocompatibility class I (MHC class I) presentation and reshaping the immunopeptidome in HR+ and triple-negative breast cancer cells. Through multiomics integration, we reveal that this remodeling is driven by retinoblastoma protein (Rb)-dependent transcriptional and chromatin reprogramming, reflected by increased H3K27 acetylation deposition and enhanced chromatin accessibility revealed by ATAC-seq. CDK4/6 inhibition dephosphorylates Rb, enhancing its interaction with BET family proteins and inducing chromatin remodeling that upregulates antigen-source transcripts. We identify immunogenic Abemaciclib-induced MHC class I peptides, including antigens derived from non-coding genomic regions, which can enhance tumor immunogenicity. These findings reveal a previously unrecognized role of CDK4/6is in shaping tumor antigenicity and suggest that combining CDK4/6is with immunotherapy could broaden antigenic targets in breast cancer.
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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 | 0.000 |
| 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".