Nagoya University researchers find local complement C3 enhances cancer immunotherapy response

Researchers at Nagoya University in Japan have discovered that the complement protein C3, when produced locally within tumors by cancer-associated fibroblasts, enhances the efficacy of cancer immunotherapy. Circulating C3 produced by the liver does not have this effect, according to a study published in Nature Communications (Nagoya University).

C3 is an evolutionarily ancient immune molecule present even in simple organisms such as sponges and jellyfish. While most C3 is made in the liver and circulates in the blood to help fight infections, its role when produced directly in tissues has been less clear. Lead author Yuki Miyai, assistant professor at the Graduate School of Medicine, Nagoya University, noted that tumors are surrounded by fibroblasts, and the function of C3 from these cancer-associated fibroblasts was previously unknown (ScienceDaily).

The team found that locally produced C3 prevents immunosuppressive myeloid cells, including M2-like macrophages, from infiltrating the tumor microenvironment. This creates conditions more favorable for the immune system to attack cancer cells during immune checkpoint blockade therapy, such as anti-PD-1 antibodies. When C3 breaks down, it generates a fragment called iC3b that acts via complement receptor 3 signaling to suppress myeloid cell entry (Nature Communications).

In mouse experiments distinguishing C3 sources, reducing liver-produced circulating C3 by 90% left anti-PD-1 therapy just as effective. In contrast, stopping C3 production by tumor fibroblasts reduced treatment efficacy, even though blood C3 levels dropped only about 9%. Tumors in mice lacking local C3 showed increased immunosuppressive cell infiltration and resistance to therapy (News-Medical).

The researchers then tested a drug that mimics C3’s blocking effect on myeloid cells in immunotherapy-resistant mouse tumors. The combination restored sensitivity to anti-PD-1 treatment and significantly extended survival. Analysis of human lung cancer samples showed parallel results: patients with higher C3 levels in the stromal tissue surrounding cancer cells had better treatment responses and longer survival. About half of those with high local C3 responded to immunotherapy, while none with lower levels did. Blood C3 levels showed no association with outcomes (SciTechDaily).

The study used conditional knockout mouse models for colorectal and lung tumors, along with clinical sample analysis. The authors plan further work to increase local C3 levels in tumors and optimize treatment timing. They suggest insights into local C3 activity could also inform understanding of wound healing and inflammation regulation. The paper is titled “Local, but not circulating, complement C3 shapes immune checkpoint blockade efficacy by controlling myeloid cell infiltration” and lists Yuki Miyai and Atsushi Enomoto among the authors (Nature Communications).