Abstract 447: A mechanism of hypoxia-induced immune escape in cancer cells
Bibliographic record
Abstract
Abstract We previously showed that hypoxia induces resistance to natural killer (NK) cell-mediated lysis in tumor cells through a mechanism that involves the shedding of NK cell-activating ligands (MICA) from the cell surface. Furthermore, we were able to block this hypoxia-induced shedding of MICA, as well as resistance to NK cell-mediated lysis, by activating NO signaling in the cancer cells. The objective of the present study was to fully elucidate this mechanism of hypoxia-induced immune escape. We used siRNA knock-down to determine the role of hypoxia-inducible factor-1 (HIF-1), a transcriptional activator of hypoxia-inducible genes, and ADAM10, a metalloproteinase known to be involved in the shedding of MICA, in the hypoxia-induced immune escape in DU145 prostate cancer cells and MDA-MB-231 breast cancer cells. Our findings revealed that in vitro exposure to hypoxia increases ADAM10 expression in a HIF-1-dependent manner, and that knock-down of ADAM10 abolishes the hypoxia-induced MICA release and resistance to NK cell-mediated lysis. Treatment of the tumor cells with low concentrations of nitroglycerin inhibited the hypoxia-induced accumulation of HIF-1α, ADAM10 up-regulation, the shedding of the NK-activating ligands, and resistance to NK cell-mediated lysis. More importantly, continuous transdermal administration of nitroglycerin (1.8 µg/h) to nude mice attenuated the growth of transplanted human DU145 prostate tumors; however, this effect of nitroglycerin was lost in mice made deficient in NK cells by treatment with anti-asialo GM1 antibody. This latter finding indicates that nitroglycerin attenuates tumor growth by sensitizing tumor cells to innate immunity. These findings are important because they indicate that nitric oxide mimetics could potentially be used as immunosensitizers in the treatment and/or prevention of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 447. doi:10.1158/1538-7445.AM2011-447
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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) | 0.002 | 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".