An immune molecule that appeared in evolution long before blood circulation may help improve cancer immunotherapy. Scientists at Nagoya University in Japan discovered that complement C3 can prevent immune-suppressing cells from building up inside tumors, but only when the protein is produced locally within the tumor. C3 traveling through the bloodstream did not influence how well treatment worked.
The findings, published in Nature Communications, suggest that reproducing this local effect could benefit patients whose tumors do not produce enough C3 naturally.
An Ancient Part of the Immune System
C3 is an evolutionarily ancient protein found even in simple animals such as sponges and jellyfish. Most C3 is made in the liver and released into the bloodstream, where it helps the immune system defend the body against infections.
Scientists know much less about what C3 does when it is produced directly inside tissues and organs.
"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," said lead author Yuki Miyai, assistant professor at the Graduate School of Medicine, Nagoya University.
Local C3 Helps the Immune System Reach Tumors
The researchers found that C3 made within tumor tissue prevents immunosuppressive myeloid cells from entering the tumor microenvironment. These cells can weaken the body's ability to attack cancer. By keeping them out, locally produced C3 gives the immune system a better opportunity to recognize and fight tumor cells.
The results point to C3 as an important regulator of cancer immunotherapy, a form of treatment that helps the immune system identify and attack cancer cells.
To determine whether C3 in the bloodstream also affected immunotherapy, the team conducted experiments in mice that allowed them to distinguish between C3 from different sources.
When the amount of liver-produced C3 was reduced by 90%, an immunotherapy drug (anti-PD-1 antibody) remained just as effective as it was in mice with normal C3 levels.
The outcome changed when researchers stopped fibroblasts inside the tumor from producing C3. Under those conditions, the same treatment became less effective, even though the amount of circulating C3 fell by only a small amount (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.
Overcoming Resistance to Immunotherapy
The team then investigated whether they could reproduce the effects of C3 in cancers that normally resist immunotherapy. They tested a drug designed to imitate the way C3 blocks myeloid cells from entering tumors.
This approach allowed immunotherapy to work against tumors that had previously resisted treatment. It also significantly extended survival in mice.
The findings could eventually help doctors identify which patients are most likely to benefit from immunotherapy. They may also lead to new treatment options for cancers that do not respond at first.
Lung Cancer Samples Support the Findings
Researchers also examined tumor samples from patients with lung cancer. Those with higher levels of C3 in the tissue surrounding cancer cells experienced better treatment results and longer survival.
About half of the patients with high local C3 levels responded to treatment. None of the patients with lower levels responded. As in the mouse studies, C3 levels in the bloodstream were not linked to treatment success.
Next Steps for Cancer Treatment Research
The researchers now plan to test ways of increasing C3 levels inside tumors and to determine the most effective timing for treatment.
They also believe that learning more about the local activity of C3 could improve understanding of other biological processes, including wound healing and the regulation of inflammation.