Saturday, June 9, 2012

Re-educating Tumor-Associated Macrophages

In an article published in 2008, Thorsten Hagemann and his fellow researchers identified a method to change tumor-associated macrophages (TAMs) into cytotoxic macrophages, which would then be able to target tumor cells as do normal MI macrophages.
Adoptive transfer of IKKβ-targeted TAMs inhibits tumor growth in vivo. Iluminescence imaging shows the amount of TAMs as a result of no treatment or treatment with dominant-negative inhibitor of IKKβ.

Hagemann et al. explained again what we already know - that the NF-κB signaling pathway is plays an important role in inflammation and tumor growth and progression. As such, they decided to target this pathway to reduce the pro-tumor effects of TAMs. They write, "When NF-κB signaling is inhibited specifically in TAMs, they become cytotoxic to tumor cells and switch to a 'classically' activated phenotype"(1).

In the main experiment highlighted in the figure above, Hagemann et al. wanted to see if using IKKβ inhibition could re-educate macrophages and thus affect tumor progression. 5 weeks into the experiment, the mice started to develop tumors with deposits throughout the peritoneum. When researchers transfered IKKβ-targeted TAMs into these tumor-bearing mice, there was a significant decrease in tumor effects compared to mice with control macrophages. Measuring the IL-10, IL-12, and TNF-α levels 14 days after macrophage transfer, they tried to identify the TAM phenotype. The mice with IKKβ-targeted macrophages showed a significant change in cytokine production with a switch to an IL-10low IL-12high and TNF-αlow profile (the usual macrophage characteristics). Thus, it was concluded that through the targeting and inhibition of IKKβ in TAMs (which had been isolated from tumors), these tumor-associated macrophages convert their phenotype from pro-tumor M2 to the anti-tumor M1 type or macrophages.

Sarra and I compared two different articles concerning immunotherapies targeting macrophages. She talks about the first article in which scientists set out to destroy the macrophages here. In doing our project, we found that this article I wrote about had a better method of dealing with macrophages, as it is not enough to simply destroy the tumor-associated macrophages. Instead, what should be done is turning the macrophages back to being anti-tumor. One issue with this article is that it did not mention exactly how they were able to do this only on the tumor associated macrophages. My guess is that the inflammation pathway they are looking at is only overexpressed in TAMs. Another thing that came to mind is that mice immune systems are very different than ours. This method may not be as effective in human models. Still, this study provides interesting perspectives on morphing TAMs to the regular macrophage phenotype and targeting the cancer cells that way.