Enhanced STAT5a activation rewires exhausted CD8 T cells during chronic stimulation to acquire a hybrid durable effector like state
Bibliographic record
Abstract
Abstract Rewiring exhausted CD8 T cells (T EX ) towards more functional states is a major goal of cancer immunotherapy but has proven challenging due to the epigenetic stability of T EX . Indeed, T EX are epigenetically programmed by the transcription factor Tox. However, epigenetic changes continue to occur as T EX transition from progenitor (T EX prog ), to intermediate (T EX int ) and terminal (T EX term ) subsets, suggesting potential developmental flexibility in mature T EX subsets. By examining the transition of T EX prog into T EX int cells, we discovered a reciprocally antagonistic circuit between Stat5a and Tox in T EX cells. Stat5-activity controlled T EX int development, antagonized Tox, and instigated partial effector biology. Stat5 was also essential for T EX reinvigoration by PD-1 blockade. Indeed, temporal induction of Stat5-activity in T EX using an orthogonal IL-2/IL2Rβ-pair fostered T EX int cell accumulation and synergized with PD-L1 blockade. Constitutive Stat5a activity (STAT5CA) antagonized Tox-dependent T EX epigenetic programming to generate a durable hybrid effector/NK-like population with enhanced tumor control. Finally, enforcing Stat5-signals in established T EX prog partially rewired the T EX epigenetic landscape towards the effector/memory lineage. Together, these data highlight therapeutic opportunities of manipulating Stat5 to rewire T EX towards a durably protective hybrid program.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".