mTOR activity and metabolic reprogramming of CD8+ T cells is impaired under hypoxia and within the multiple myeloma bone marrow
Bibliographic record
Abstract
ABSTRACT: Novel therapies for multiple myeloma (MM) aim to engage antitumor functions of T cells. However, evidence indicates these functions are limited within the bone marrow (BM) environment. This is relatively hypoxic in health, and studies indicate widespread hypoxia in MM. In this study, CD8+ T-cell responses to stimulation were assessed under hypoxia, which identified that activation, proliferation, and interferon-gamma (IFN-γ) secretion were profoundly suppressed, while cytotoxicity and tumor necrosis factor-α (TNF-α) expression were unaffected. These changes occurred alongside decreased mechanistic target of rapamycin (mTOR) activity and expression of c-Myc, which drives T-cell metabolic reprogramming upon stimulation. Consistently, hypoxic CD8+ T cells demonstrated decreased activation-induced glycolysis and mitochondrial glutamine oxidation. Mechanistically, this was linked to elevated BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) expression under hypoxia, and reciprocally decreased abundance of its interaction partner, Ras homolog enriched in brain (Rheb), an important mTOR activator. Assessment of BCMA×CD3 bispecific antibody activity confirmed impaired capacity to elicit CD8+ T-cell activation, IFN-γ expression, proliferation, and altered memory differentiation under hypoxia, although initial target cell killing was unaffected. Finally, assessment of BM CD8+ T cells from patients with MM identified decreased proliferation, c-Myc, and Rheb expression compared with peripheral blood cells, alongside elevated BNIP3, confirming mechanistic features of hypoxic exposure in this environment. Taken together, the findings indicate potential for BM hypoxia to influence efficacy of T cell-directed therapies for MM.
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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".