Ancient immune protein C3 boosts cancer immunotherapy within tumors

An ancient molecule that existed long before the blood circulation system evolved, has been found to support cancer immunotherapy. Researchers at Nagoya University in Japan found that complement C3 protein acts inside tumors to prevent the accumulation of immunosuppressive cells, but only when produced inside the tumor. C3 circulating in the blood did not affect treatment outcomes. Published in Nature Communications, the findings suggest that artificially recreating this effect can help patients with tumors that do not naturally produce enough of this protein. 

C3 protein is extremely old in evolutionary terms and present in simple organisms such as sponges and jellyfish. It is produced mainly in the liver and plays a vital role in the body's immune system, travelling through the blood to protect against infections. However, its role when produced locally in tissues and organs is largely unknown. 

Cancer tumors are surrounded by normal cells called fibroblasts. Until now, the role of complement C3 produced by these cancer-associated fibroblasts within tumor tissue was not known."

Yuki Miyai, lead author, assistant professor, Graduate School of Medicine, Nagoya University

The researchers discovered that C3 produced in tumor tissue prevents immunosuppressive myeloid cells from infiltrating the tumor microenvironment. The body's immune defenses then have a better chance of fighting cancer. The results identify C3 as a new factor that regulates the efficacy of cancer immunotherapy - cancer treatment that helps the immune system recognize and attack cancer cells. 

To test whether C3 in the blood was also responsible for immunotherapy effectiveness, the research team used mice to separate the roles of C3 according to its sources. When C3 produced by the liver was decreased by 90%, a drug that helps the immune system attack tumors (anti-PD-1 antibody) worked just as well as it did in mice with normal C3 levels. 

However, when C3 production by fibroblasts within the tumor was stopped, the same drug became less effective, even though circulating C3 in the blood changed very little (a 9% decrease). 

"What determined the efficacy of the immunotherapy treatment was not the C3 in the blood, but the local C3 produced at the tumor site. When this C3 breaks down, it forms a fragment called iC3b that stops harmful myeloid cells from entering the tumor. As a result, immunotherapy is more likely to work," Miyai explained. 

To test if recreating the effect of C3 could help in cancers that do not respond to immunotherapy, the researchers tested a drug that mimics the blocking effect of C3 on myeloid cells. This allowed immunotherapy to work in tumors that had previously resisted treatment and significantly extended survival in mice. The results may help doctors predict which patients immunotherapy can help and offer new options for cancers that do not initially respond to it. 

Tumor samples from lung cancer patients were also analyzed. Patients with higher C3 levels in the tissue surrounding cancer cells had better treatment outcomes and survival rates. About half responded, compared to none of the patients with lower C3 levels. Again, C3 levels in the blood made no difference. 

Next, the research team will conduct experiments to boost local C3 levels and identify the best timing for treatment. The authors believe that understanding how this protein works could shed light on other biological processes, such as how the body heals wounds and manages inflammation.