Turning the Tables on Tumors

Immune cells (red and green) are recruited to fight tumor cells (blue) after microRNA depletion in macrophages. 

M. SQUADRITO, C. BAER, M. DE PALMA

Certain immune system cells known as macrophages normally rid the body of unwanted substances, but can be converted by cancerous cells to allow tumors to expand instead. A recent study has shown how to switch the macrophages back in mouse models, opening up possible new therapeutic routes. 

The macrophages in question come in two versions, called M1 and M2. The latter promotes tissue growth by sprouting new blood vessels and keeping the broader immune system at bay—ideal for healing a wound after an injury, but unfortunately also optimal for the spread of malignant tissues. “Indeed, tumors can be defined as wounds that never heal,” said Michele De Palma, a cancer researcher at the Swiss Federal Institute of Technology in Lausanne and senior author of the study. 

In contrast to M2 macrophages, M1 macrophages alert the immune system to send in reinforcements and kill off potential pathogens. To avoid this fate, tumors release chemicals that preferentially turn M1 macrophages into the M2 variety. Most of the tumor-associated macrophages thus behave as the self-serving M2 version. 

De Palma and his colleagues aimed to reverse this process. The scientists focused on molecules called microRNAs which influence macrophage form and function. Using genetic engineering, the researchers deleted an enzyme in macrophages that is necessary for producing several microRNAs, including one known as Let-7. When levels of Let-7 were decreased, more macrophages functioned as the desirable M1 type. Tumors in the treated mice shrank, and these animals had fewer instances of meta-stasis—when cancer cells leave the original tumor site and settle elsewhere in the body, an advanced stage of disease that often leads to death. 

In light of these findings, De Palma’s team hopes to develop drugs that shut down Let-7 in human tumor-associated macrophages. The drugs must be specifically targeted to avoid interfering with macrophages elsewhere in a patient’s body. “You do not want to block Let-7 in other cells,” said De Palma, “as this microRNA may have important functions.” Regardless, this study points to tumor-associated macrophages as a new avenue of attack against cancer. (Nature Cell Biology

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