Protein Fragment Promotes Anti-Cancer Response

Free C3d protein, a fragment of the third component of complement, has been found to prevent cancer cells from avoiding the body's immune response and has potential to be developed into a chemotherapeutic agent for cancer treatment.

Tumors escape the immune system by engaging T- cell checkpoint regulators and expanding regulatory T-cells (Tregs), among other mechanisms. The molecular factors that control these mechanisms are unknown.

Investigators at the University of Michigan reported in the May 4, 2017, online edition of the Journal of Clinical Investigation Insight that free C3d - inside tumor cells or associated with irradiated tumor cells and unattached to antigen - recruited, accelerated, and amplified antitumor T-cell responses, allowing the immune system to reverse or even to prevent tumor growth. These findings were obtained from studies on mice melanoma and lymphoma models.

C3d enhanced antitumor immunity independently of B-cells, NK cells, or antibodies, but it did so by increasing tumor infiltrating CD8+ lymphocytes, by depleting Tregs, and by suppressing expression of programmed cell death protein 1 (PD-1) by T-cells. These properties of C3d appeared to be specific for the tumor and dependent on complement receptor II, and they incurred no obvious systemic toxicity.

"Our cancer therapy blocks tumor-induced immunosuppression. Because it is natural, it does not have adverse effects as far as we know," said senior author Dr. Marilia Cascalho, associate professor of surgery, microbiology, and immunology at the University of Michigan. "The most recent success in cancer immunotherapy is with agents that block the inhibition of the immune system. Even though there has been success with immunotherapy, the problem is that immunotherapy is not specific. The drugs work everywhere, so there are many secondary effects. Our cancer therapy takes an entirely new path to blocking tumor-induced immunosuppression. It is different because when free C3d was injected into cancer cells in the research, it did not appear to have side effects."