Adjusting Macrophage Polarization as a Basis for Cancer Immunotherapy

Macrophage polarization is a hot topic of late. The innate immune cells known as macrophages are responsible for a wide range of duties that include destroying errant cells, attacking pathogens, cleaning up waste and debris, and participation in tissue regrowth and regeneration. The polarization of a macrophage describes its state and inclination as to which of those duties it undertakes: M1 macrophages are aggressive and inflammatory, while M2 macrophages tend towards participation in the gentler processes of rebuilding and regeneration. Many of the common inflammatory age-related conditions appear to be characterized by too many M1 macrophages and too few M2 macrophages. Methods by which that balance can be shifted seem promising as a basis for therapy.

Cancer is a different story, however, as is often the case. Many of the issues seen in aging can actually be helpful when it comes to the short-term goals of shutting down and eliminating cancerous tissue. Forcing cancerous cells into senescence is a viable strategy, for example, even though researchers know that senescent cells are one of the root causes of aging, and are working on ways to remove them from normal aged tissues. In this case, the problem of too many M1 macrophages is actually a desirable goal when it comes to attacking cancer. The researchers here are clearly achieving good results via encouraging more macrophages to take up the M1 phenotype in the cancer environment.

Much cancer immunotherapy research has focused on harnessing the immune system's T cells to fight tumors, "but we knew that other types of immune cells could be important in fighting cancer too." Now researchers report that in preclinical models they can amplify macrophage immune responses against cancer using a self-assembling supramolecule. As immune cells, macrophages usually eat foreign invaders including pathogens, bacteria, and even cancer cells, but one of the two types do not always do so. Macrophage type M1s are anti-tumorigenic, but M2s can be recruited by tumor cells to help them grow. Also, tumor cells overexpress a protein that tells the macrophages, "don't eat me." In this way, pro-tumorigenic macrophages may make up 30 to 50 percent of a tumor's mass.

"With our technique, we're re-programming the M2s into M1s by inhibiting the M2 signaling pathway. We realized that if we can re-educate the macrophages and inhibit the 'don't eat me' protein, we could tip the balance between the M1s and M2s, increasing the ratio of M1s inside the tumor and inhibiting tumor growth." The researchers used a multi-component supramolecular system that self-organizes at the nanoscale to deliver an antibody inhibitor plus a drug inside the tumor. This is the first time anyone has combined a drug that targets M2 macrophages and an antibody that inhibits the 'don't eat me signal' in one delivery system.

The researchers tested the supramolecular therapeutic in animal models of two forms of cancer, comparing it directly with a drug currently available in the clinic. Mice that were untreated formed large tumors by Day 10. Mice treated with currently available therapies showed decreased tumor growth. But mice treated with the new supramolecular therapy had complete inhibition of tumor growth. The team also reported an increase in survival and a significant reduction in metastasis. The next steps are to continue testing the new therapy in preclinical models to evaluate safety, efficacy and dosage.


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