Interferon Gamma Promotes Anticancer Activity in Macrophages, Enhancing the Immune Response

New research aims to flip M2 macrophages, which promote the growth of cancer, into the M1 type, which may aid the immune system in clearing cancer. This work, done in mouse models, was published in Cancer Research.1

Macrophages are differentiated to specialize in either wound repair (M2 type) or wound sterilization (M1). Cancers encourage macrophages to become M2 type to promote its growth.

"The basic message we're trying to convey is that turning those M2 macrophages into a more M1 phenotype has beneficial effects in promoting antitumor immunity," said Laurel Lenz, PhD, investigator at the University of Colorado (CU) Cancer Center, professor in the Department of Microbiology and Immunology at the CU School of Medicine in Aurora, and coauthor of the study.

The researchers explained that, in mouse models of cancer, encouraging a high ratio of M1: M2 macrophages can “slow or stop cancer growth.”

This research found that, in the presence of the cytokine interferon gamma, macrophages took on the M1 phenotype.

"Interferon gamma has been explored as a possible therapeutic agent,” Lenz explains, but there are problems with its use. The cytokines mediate hundreds of effects, and some are not very comfortable for patients.

One approach is to improve the sensitivity of cells to the interferon gamma that already exists in the body. The aim would be to prevent macrophages from losing their sensitivity to interferon gamma. Another approach might be to augment interferon gamma in the tumor tissue only, so its effects stay localized.

"The immune system's killer cells produce interferon gamma and one promising strategy is to get them to the tumor and activated in the right way," Lenz says.

Existing immunotherapies aim to recruit cytotoxic T cells, which are killer cells, to recognize and attack tumor tissue. This activation has interferon gamma as a byproduct at the tumor site, and so macrophages there take the M1 and not the M2 phenotype.

"Cytotoxic T cells can directly kill tumor cells. But they also produce interferon gamma. Both are likely contributing to the antitumor effect," said Lenz. "By devising approaches to tune macrophages in the right way, we hope to further improve immunotherapies."

REFERENCE

1. Mills CD, Lenz LL, Harris RA. A breakthrough: macrophage-directed cancer immunotherapy. Cancer Res. 2016;76(3):513-516.

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