Normal cells that have transformed into cancer cells produce and display large amounts of proteins called tumor- and leukemia-associated antigens (TAA). Although immune cells recognize TAAs it has been difficult to develop immunotherapies for humans based on these interactions, in part because many normal cells and tissues produce small amounts of TAAs and the body has a certain amount of self-tolerance that prevents a vigorous immune attack.

Dr. Matthias Theobald from Johannes Gutenburg-University in Mainz, Germany, and colleagues used sophisticated genetic techniques to circumvent this self-tolerance and essentially redirect key human immune cells. Specifically, the researchers focused on the p53 tumor suppressor protein that is mutated in the majority of human cancers. Immune self-tolerance to p53 exists because of low levels of wild-type p53 that are expressed by normal cells.

The researchers used special mice genetically engineered that lack the normal action of CD8 cells required for development of self-tolerance to generate an immune cell receptor (TCR) specific for tumor-associated p53. The gene for this receptor was then transferred to human immune cells and resulted in redirected CD4+ Th and CTL immune cells that aggressively attacked tumor cells.

According to Dr. Theobald, "Our study on the intentional redirection of human CD4+ Th cells and high-avidity CD8 CTL by the delivery of genes encoding a single CD8-independent, high-affinity p53A2.1-specific TCR lays the foundation for the exploitation of this approach for a novel, broad-spectrum immunotherapy of malignant disease."

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The success of this cell-to-cell communication is crucial. When the signals from the stromal cells are blocked, the stem cell population is gradually lost. When the signals are on all the time, or specific genes in the daughter cells are mutated, every daughter cell acts like a stem cell and the future eggs are lost.

"That stem cells are maintained by blocking gene expression suggests that the microenvironment, or niche, captures the cells and prevents them from differentiating," Dr. McKearin said. "Cells that are poised to differentiate do not, simply because of their niche."

Dr. McKearin said that in addition to their influence on stem cells, local environments or niches may influence the spread of cancer.

"Specific types of cancer often metastasize to specific other organs," he said.  "For example, prostate cancer cells that respond to certain growth factors may metastasize to bone, but not liver, because they can respond to external factors in the bone niche, but not the liver niche."

The other contributor to this study is Dr. Dahua Chen, instructor in molecular biology at UT Southwestern and lead author.

The study was funded by the National Institutes of Health.

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