The effect of hypoxia on the natural killer activity of human peripheral blood lymphocytes against cancer cells
Bibliographic record
Abstract
Proc Amer Assoc Cancer Res, Volume 47, 2006 627 Introduction and Objective: The potential role of natural killer (NK) and lymphokine activated killer (LAK) cells in cancer immunotherapy is expanding and subsequent investigation of tumor escape mechanisms of innate immunity is an exciting area of basic science and clinical inquiry. Tumour hypoxia has been shown to be associated with malignant progression in cancer cells and an independent prognostic indicator of poor clinical outcome for patients with various cancers. We have previously shown that this hypoxia induced progression can be attenuated by low concentrations of nitric oxide (NO) mimetic agents. We therefore postulate that a hypoxic environment may also have a significant effect on the ability of immune cells to target and kill tumor cells. We determine the effect of hypoxia on natural killer cell cytotoxicity. Furthermore, we determine the role of NO to improve prostate cancer cell killing by circulating immune cells. Methods: Two human prostate cancer cell lines PC3 and DU145, as well as a natural killer cell (NK) sensitive leukemia cell line K562, were used for cytotoxicity experiments. Cells were cultured in hypoxic (1% O2) or standard (20% O2) conditions for 24 hours prior to exposure to effector immune cells. Cytotoxicity was assessed using a standard four hour chromium release assay to measure NK activity of fresh human peripheral blood lymphocytes, as well as IL-2 stimulated LAK cells. Furthermore, we investigated the effect of hypoxia on the tumor expression of ligands (MHC class 1 chain related molecules (MIC)) for NK activating receptors with flow cytometry. To determine the ability of NO to modulate effects of tumor hypoxia, we cultured the cell lines with an NO mimetic, GTN, to determine if it could inhibit the hypoxic effects on tumor cell killing. Results: Results of the cytotoxicity assays reveal that culturing cell lines in a low oxygen environment will significantly decrease NK and LAK cell killing. This reduction of cytotoxicity was found to be associated with a tumor cell shedding of MIC A, B molecules. As well, in both the leukemia and prostate cancer cell lines, the addition of low molar concentrations of GTN did significantly attenuate the hypoxia-associated decreased cell killing. Conclusions: These findings indicate hypoxia leads to cellular adaptive responses of prostate cancer cells which interfere with immune effector cell killing, due at least in part by tumor shedding of MIC. These hypoxia related effects may be inhibited by the addition of low concentrations of nitric oxide mimetics. These novel findings suggest that manipulation of nitric oxide signalling may be a beneficial adjuvant in cell based adoptive immunotherapy protocols for prostate cancer.
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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) | 0.003 | 0.001 |
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".