Functional Plasticity of Gamma Delta T Cells and Breast Tumor Targets in Hypoxia
Bibliographic record
Abstract
Interactions between immune and tumour cells in the tumour microenvironment (TME) often impact patient outcome, yet remain poorly understood. In addition, the effects of biophysical features such as hypoxia [low oxygen (O2)] on cells within the TME may lead to tumour evasion. Gamma delta T cells (γδTc) naturally kill transformed cells and are therefore under development as immunotherapy for various cancers. Clinical trials have proven the safety of γδTc immunotherapy and increased circulating γδTc levels correlate with improved patient outcome. Yet, the function of γδTc tumor infiltrating lymphocytes (TIL) in human breast cancer remains controversial. Breast tumours can be highly hypoxic, thus therapy must be effective under low O2 conditions. We have found increased infiltration of γδTc in areas of hypoxia in a small cohort of breast tumours; considering their inherent plasticity, it is important to understand how hypoxia influences γδTc function. In vitro, the cell density of expanded primary healthy-donor blood-derived human γδTc decreased in response to hypoxia (2% O2) compared to normoxia (20% O2). However, the secretion of MIP1α/MIP1β, RANTES and CD40L by γδTc were increased after 40 hours in hypoxia compared to normoxia concomitant with the stabilization of Hypoxia Inducible Factor 1-alpha (HIF1α) protein. Mechanistically, we determined that NKG2D on γδTc and the NKG2D ligand MICA/B on MCF-7 and T47D breast cancer cell lines are important for γδTc cytotoxicity, but that MIP1α, RANTES and CD40L do not play a direct role in cytotoxicity. Hypoxia appeared to enhance the cytotoxicity of γδTc such that exposure for 48 hours increased cytotoxicity of γδTc against breast cancer cells that were maintained in normoxia; conversely, breast cancer lines incubated in hypoxia for 48 hours prior to the assay were largely resistant to γδTc cytotoxicity. MICA/B surface expression on both MCF-7 and T47D remained unchanged upon exposure to hypoxia; however, ELISAs revealed increased MICA shedding by MCF-7 under hypoxia, potentially explaining resistance to γδTc cytotoxicity. Despite enhanced γδTc cytotoxicity upon pre-incubation in hypoxia, these cells were unable to overcome hypoxia-induced resistance of MCF-7. Thus, such resistance mechanisms employed by breast cancer targets must be overcome to develop more effective γδTc immunotherapies.
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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) | 0.001 | 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".