Tuning Macrophages for Immunotherapy

The term macrophage comes from the Greek words makros, meaning large, and phagein, meaning to eat. Macrophages patrol the body seeking any cell types that do not display the proper protein surface markers and consume these foreign intruders in a process called phagocytosis. This process is useful for removing a variety of foreign substances, including potentially cancerous cells. However, cancerous cells are able to exploit the body’s immune system to prevent destruction by macrophages and possibly encourage proliferation of the cancerous cells.

Differentiation of monocytes into macrophages

During initial differentiation of macrophages from monocytes, macrophages can differentiate into either M1 macrophages or M2 macrophages. M1 macrophages are considered kill-type macrophages. In the course of an infection, these are the macrophages which will kill the foreign intruder and sterilize the wound. M1 macrophages accomplish this task by metabolizing arginine to nitric oxide, which is cytotoxic to invading cells. M2 macrophages are considered repair-type macrophages. In the course of an infection, these are the macrophages that will promote new growth of the surrounding tissue to repair the damage of the infection. M2 macrophages accomplish this task by metabolizing arginine to ornithine, which is critical in the regulation of cell proliferation.

Macrophages in cancer therapy

Cancer cells have a means of suppressing M1 macrophages while supporting M2 macrophages. The lack of M1 macrophages results in cancer cells not being destroyed by the body’s immune system, and the abundance of M2 macrophages promotes the growth and proliferation of the tumor, promoting its survival. Studies have shown that patients who have a higher ratio of M1 macrophages compared to M2 macrophages are much less likely to get cancer. Furthermore, cancer proliferation rates in mouse models where the mice have a higher ratio of M1 macrophages to M2 macrophages are much slower in comparison to cancer proliferation rates in mice with a lower ratio of M1 macrophages to M2 macrophages.

As such, a promising breakthrough in cancer immunotherapy may be on the horizon if research can determine an effective and efficient means of increasing the ratio of M1 macrophages compared to M2 macrophages. To do so, two feasible options have been proposed. The first option would be to reprogram the M2 macrophages back to their more stem-cell-like state, and then promote differentiation of the cells into the M1 phenotype. The second option would be to allow the M2 macrophages to naturally die off while promoting the differentiation of new macrophages into the M1 phenotype.

Macrophages can be stimulated to differentiate into M1 macrophages through the introduction of interferon gamma; however, simply adding additional interferon gamma can produce a number of unwanted side effects due to its wide use in the body. Additionally, too much stimulation with interferon gamma may potentially reduce the sensitivity of macrophage differentiation by the agent, so adding more is not the ideal solution.

Alternatively, it may be possible to modify the macrophages to be more sensitive to interferon gamma, allowing for more M1 differentiation without increasing the levels of interferon gamma. Additionally, it may be possible to simply increase interferon gamma directed at the site of the tumor to localize the differentiation of macrophages without the widespread impact of increased interferon gamma throughout the body. Cytotoxic T cells have the ability to directly kill the tumor cells. However, they also produce interferon gamma, which increases M1 macrophage differentiation, further contributing to the anti-tumor effects of the immune response. By further enhancing the activity of both the T cells and the macrophages, an ideal immunotherapy could potentially be harnessed.

Lonza CD14+ Monocytes are a mixture of all the various subsets present in the donor at the time of blood draw. These cells have been shown to differentiate into macrophages with the proper stimuli and are available from various donors. 

Please contact Lonza Scientific Support for more information. In addition, if you have large-volume needs, we may be able to do custom cell isolations through our CellBio Services.