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 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".