A Novel Type of Immunotherapy May Eliminate All Advanced Tumor Cells

Immunotherapy has gained full attention around the world, which gradually becomes the mainstream cancer treatment. As the key executor of the downstream effects of the immune response, macrophages play an important role in the immune response and have super "plasticity".

Recently, researchers from Georgia State University published a groundbreaking study titled Intratumoral SIRP?-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy in Nature Communications about a newly developed type of immunotherapy based on macrophages, which can effectively treat a variety of advanced cancers.

Macrophages are like scouts of the human body, which will swallow and destroy potential threats. However, cancer cells are cunning in that they often disguise themselves as normal cells and escape the immune surveillance of macrophages through the common selection mechanism that normal cells rely on to enhance their ability to divide, thereby suppressing the body's immune response.

The culprit for this escape phenomenon is a receptor called regulatory protein alpha (SIRP?), an inhibitory regulator of bone marrow leukocyte expression, whose typical function is to interact with the self-identifying marker CD47 to inhibit the function of phagocytes, severely limiting the tumor-killing immunity induced by radiotherapy (RT).

Therefore, to prevent macrophages from continuing to injure "the innocent", the researchers developed a macrophage therapy based on SIRP? deficiency to fight cancer, and constructed an in vivo colorectal cancer model of MC38 for verification.

Studies showed that local radiotherapy and chemotherapy have cured colorectal cancer in SIRP?-deficient (SIRP? -/-) mice with advanced tumors, without obvious long-term adverse reactions, and can show a lifespan similar to that of healthy mice (about 18 months). This shows that macrophages knocked out of the SIRP? gene can initiate a powerful immune response against cancer by triggering inflammation and activating tumor-specific T cells, which can minimize the adverse effects on healthy cells.

In order to determine whether the long-term anti-tumor immunity in the treated SIRP?-deficient mice has generated, the researchers performed tumor re-transplantation experiments on SIRP? -/- mice from which colon cancer had been eradicated, and re-inoculated MC38 cells into the mice. Surprisingly, cancer cells did not proliferate in mice, which indicates that the mice may have acquired long-term humoral anti-tumor immunity.

In addition, the researchers also found that when wild-type mice successfully inoculated with MC38 cells were injected with serum from tumor eradicated SIRP?

• mice, the spread of cancer cells were successfully inhibited, which shows that the serum of SIRP? -/- mice from which tumors have been eradicated the ability to prevent the formation of new tumors.

All in all, this study shows that SIRP? is the main manipulator of tumor microenvironmental immunity, and that this new technology combined with radiotherapy and chemotherapy may become a "pan-cancer therapy" that guides humans against all cancers.

So far, the treatment has been tested against the entire NCI-60 cancer portfolio, including 60 different human tumor cell lines, such as leukemia, melanoma, lung cancer, colon cancer, brain cancer, ovarian cancer, breast cancer, and prostate cancer, and kidney cancer, showing significant effects.

Currently, researchers are applying to the U.S. Food and Drug Administration (FDA) for approval of the therapy as an investigational new drug, and plans to conduct human clinical trials in 2022. Not only that, this new treatment has also received funding from the National Cancer Institute, Georgia Research Alliance, and Biolocity.

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