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Chemotherapies Undermine Effects, Aid Angiogenesis

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By Anette Breindl
Science Editor

The relationship between cancer, cancer treatments, inflammation and immunity had another layer of complexity added to it with the report this week that chemotherapy can contribute to promoting tumor growth via activating the inflammasome in some types of immune system cells, which ultimately led to angiogenesis.

The effects of cancer drugs on the immune system are multifaceted, to say the least, and can cut both ways.

Immune-stimulating targeted therapeutics Provenge (sipuleucel-T, Dendreon Inc.) and Yervoy (ipilimumab, Bristol-Myers Squibb Co.) have as their goal to activate the immune system against cancer cells. Recent work has also shown that some kinds of chemotherapy can help immune activation, as dying tumor cells release antigens that cross-prime the immune system.

Simultaneously, though, chemotherapy can suppress the immune system. With its cells that divide rapidly in response to pathogens, the immune system is often among the collateral damage of chemotherapy.

The new findings showed that two commonly used chemotherapies, 5-fluorouracil or 5-FU and gemcitabine, can undermine their own antitumor effects not just by killing immune system cells. The drugs can also activate the inflammasome and, ultimately, angiogenesis.

The inflammasome is a group of proteins that is activated by Nod-like receptors – innate immune system sensors that are similar to Toll-like receptors, though they are in the cytoplasm rather than the membrane. The inflammasome controls the release of several proinflammatory interleukins, including interleukin-1beta.

In their studies, which appeared in the Dec. 2, 2012, advance online edition of Nature Medicine, senior author Francois Ghiringhelli of the INSERM Institute and his team focused on one particular immune system type, myeloid-derived suppressor cells.

The inflammasome, Ghiringhelli told BioWorld Today, also plays a role in several other immune system cell types, including macrophages and dendritic cells. But "we have demonstrated that only [myeloid-derived suppressor cells] are affected by chemotherapy at the dosage used for patients," and so his team focused on those cells.

In previous studies, Ghiringhelli and his colleagues had shown that 5-FU depletes myeloid-derived suppressor cells, and the depletion – because the cells themselves are immune suppressors that are activated by tumor cells – enhances antitumor immunity.

But in the new study, Ghiringhelli and his team found that treatment with 5-FU also activated caspase in myeloid-derived suppressor cells of cancer patients, and that this effect decreased its tumor-fighting power.

Caspase plays important roles in apoptosis, but also in inflammation. In the experiments now published in Nature Medicine, caspase activated the inflammasome. In knockout mice that either had no caspase, or lacked the important inflammasome component Nrlp3, 5-FU treatments improved the survival chances of mice with xenografted tumors.

The cytokines released by the inflammasome – notably, IL-1beta – ultimately affected helper T cells, stimulating them to release another interleukin, IL-17. And IL-17, in turn, can turn on gene expression programs that promote angiogenesis, the formation of blood vessels that tumors need to grow.

The finding that chemotherapies, in particular 5-FU, can activate the inflammasome and so limit its own effects breaks new ground scientifically.

The team tried to modulate the dose of 5-FU to see whether there were drug levels that preserved the chemotherapy's positive effects on antitumor immunity – that is, its depletion of myeloid-derived suppressor cells – without activating the inflammasome. But at least within their experimental framework, you can't have one without the other.

So from a clinical point of view, Ghiringhelli said, the work suggested "combinations of 5FU and inhibitor of IL-1beta or IL-17 to enhance its efficacy. . . . The next step is to generate a clinical trial to test the efficacy of the combination of 5FU and IL1 inhibition." Ghiringhelli and his team are currently working on in initiating such a trial.