Ancient Immune Protein C3 Boosts Cancer Immunotherapy When Produced Inside Tumors
Key Insights
Researchers at Nagoya University found that complement C3 (search) protein, when produced locally by fibroblasts inside tumors, limits the infiltration of immunosuppressive cells into the tumor microenvironment.
C3 circulating in the blood did not affect treatment outcomes; only tumor-local production shaped anti-tumor immunity and improved immunotherapy response.
In preclinical models, a drug blocking suppressive cell infiltration converted immunotherapy-resistant tumors into responsive ones, suggesting a new therapeutic strategy.
An ancient immune protein that predates the evolution of the circulatory system has been found to play a critical role in boosting the effectiveness of cancer immunotherapy—but only when it is produced locally within tumors. Researchers at Nagoya University in Japan have demonstrated that complement C3 (search) protein, produced by cancer-associated fibroblasts in the tumor microenvironment (TME), limits the trafficking of immunosuppressive cells and thereby enhances anti-tumor immune responses. The findings, published in Nature Communications, open new avenues for overcoming immunotherapy resistance in patients whose tumors do not naturally produce sufficient C3.
The complement system is an ancient arm of innate immunity, comprising over 50 plasma proteins that rapidly target foreign pathogens and trigger inflammatory responses. Complement C3 (search), one of the most abundant complement proteins, is evolutionarily conserved and can be found in organisms as simple as sponges and jellyfish. It is primarily produced in the liver and circulates through the bloodstream, where it tags infected cells with molecules for immune cells to identify and destroy. However, its role when produced locally in tissues and organs has remained largely unknown.
C3's Local Role in the Tumor Microenvironment
Cancer tumors are surrounded by normal cells called fibroblasts. Until now, the role of complement C3 (search) produced by these cancer-associated fibroblasts within tumor tissue was not understood. Yuki Miyai, lead author and assistant professor in the Graduate School of Medicine at Nagoya University, and colleagues set out to investigate this question.
The research team, led by Dr. Atsushi Enomoto, a professor in the Graduate School of Medicine for Neurological Disease and Cancer Division at Nagoya University, found that complement C3 (search) shapes the TME by limiting the infiltration of suppressive immune cells. In the context of cancer, certain cells that normally attack tumors can become polarized and begin suppressing other immune cells—a process driven by tumor-secreting growth factors and molecules. Enomoto and his team demonstrated that C3 restricts the trafficking of these suppressive cells into the TME, thereby improving immunotherapy outcomes.
Critically, this activity of complement C3 (search) only occurs when the protein is produced inside the tumor. C3 circulating in the blood did not affect tumor growth or treatment outcomes. The group further demonstrated that complement C3 produced by fibroblasts in the TME improved immunotherapy responses compared to tumors without fibroblasts.
From Bench to Potential Bedside
To explore the therapeutic implications, the researchers used a drug that blocks the infiltration of suppressive cells—mimicking the effect of complement C3 (search) in the tumor—in preclinical animal cancer models. Mice implanted with tumors were treated with the reagent. Strikingly, mice that were previously resistant to immunotherapy became responsive to treatment after administration of the drug.
This work demonstrates the impact that complement C3 (search) has on the immune system and how it can be leveraged to improve patient outcomes. It also suggests that artificially creating complement C3 and administering it within the tumor, or alternatively blocking suppressive cell infiltration, could be offered in combination with current standard-of-care treatments. Researchers hope to continue investigating this mechanism and develop drugs for clinical use.
The study highlights a previously unrecognized, evolutionarily ancient mechanism by which local complement production can be harnessed to reshape the tumor microenvironment and overcome immunotherapy resistance.