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Pulling RANK on Cancer: Blocking Aire-Mediated Central Tolerance to Enhance Immunotherapy.

ABSTRACT: A major breakthrough in cancer treatment occurred with the development of strategies that overcome T-cell tolerance toward tumor cells. These approaches enhance antitumor immunity by overcoming mechanisms that are normally in place to prevent autoimmunity but simultaneously prevent rejection of tumor cells. Although tolerance mechanisms that restrict antitumor immunity take place both in the thymus and periphery, only immunotherapies that target peripheral tolerance mechanisms occurring outside of the thymus are currently available. We review here recent gains in our understanding of how thymic tolerance mediated by the autoimmune regulator (Aire) impedes antitumor immunity. It is now clear that transient depletion of Aire-expressing cells in the thymus can be achieved with RANKL blockade. Finally, we discuss key findings that support the repurposing of anti-RANKL as a cancer immunotherapy with a unique mechanism of action.

SUBMITTER: Su MA

PROVIDER: S-EPMC6550349 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Pulling RANK on Cancer: Blocking Aire-Mediated Central Tolerance to Enhance Immunotherapy.

Su Maureen A MA Anderson Mark S MS

Cancer immunology research 20190601 6

A major breakthrough in cancer treatment occurred with the development of strategies that overcome T-cell tolerance toward tumor cells. These approaches enhance antitumor immunity by overcoming mechanisms that are normally in place to prevent autoimmunity but simultaneously prevent rejection of tumor cells. Although tolerance mechanisms that restrict antitumor immunity take place both in the thymus and periphery, only immunotherapies that target peripheral tolerance mechanisms occurring outside ...[more]

PMID: 31160305

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Project description:Status within social hierarchies has great effects on the lives of socially organized mammals. Its effects on human behavior and related physiology, however, is relatively little studied. The present study investigated the impact of military rank on fairness and behavior in relation to salivary cortisol (C) and testosterone (T) levels in male soldiers. For this purpose 180 members of the Austrian Armed Forces belonging to two distinct rank groups participated in two variations of a computer-based guard duty allocation experiment. The rank groups were (1) warrant officers (high rank, HR) and (2) enlisted men (low rank, LR). One soldier from each rank group participated in every experiment. At the beginning of the experiment, one participant was assigned to start standing guard and the other participant at rest. The participant who started at rest could choose if and when to relieve his fellow soldier and therefore had control over the experiment. In order to trigger perception of unfair behavior, an additional experiment was conducted which was manipulated by the experimenter. In the manipulated version both soldiers started in the standing guard position and were never relieved, believing that their opponent was at rest, not relieving them. Our aim was to test whether unfair behavior causes a physiological reaction. Saliva samples for hormone analysis were collected at regular intervals throughout the experiment. We found that in the un-manipulated setup high-ranking soldiers spent less time standing guard than lower ranking individuals. Rank was a significant predictor for C but not for T levels during the experiment. C levels in the HR group were higher than in the LR group. C levels were also elevated in the manipulated experiment compared to the un-manipulated experiment, especially in LR. We assume that the elevated C levels in HR were caused by HR feeling their status challenged by the situation of having to negotiate with an individual of lower military rank. This would be in line with the observation that unequally shared duty favored HR in most cases. We conclude that social status, in the form of military rank affects fairness behavior in social interaction and endocrine levels.

Dataset Information

Pulling RANK on Cancer: Blocking Aire-Mediated Central Tolerance to Enhance Immunotherapy.

Publications

Pulling RANK on Cancer: Blocking Aire-Mediated Central Tolerance to Enhance Immunotherapy.

Similar Datasets

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