C3d Protein Reverses Tumor-Mediated Immune Suppression

Vaccination with the immune complement component C3d protein blocks tumor-mediated immunosuppression, enhancing antitumor immune response-an “entirely new” approach to countering tumor immune suppression and evasion, according to authors of a new preclinical study of mice with lymphoma and melanoma.

Free C3d reversed tumor immune suppression and led to remarkable 80% to 90% reductions in tumor burden among mice with murine lymphoma and melanoma, the team reported. The findings were published in the journal JCI Insight.

“Our cancer therapy blocks tumor-induced immunosuppression,” said coauthor Marilia Cascalho, MD, PhD, associate professor of surgery, microbiology, and immunology at University of Michigan Medicine in Ann Arbor, Michigan. “The biggest surprise is that free C3d cancer vaccination produced long-lived antitumor immunity.”

The work stemmed from unexpected findings in human immunodeficiency virus vaccine research.

Free, circulating C3d enhanced antitumor immunity “independently of B cells, NK [natural killer] cells, or antibodies, but it does so by increasing tumor infiltrating CD8-positive lymphocytes, by depleting Tregs [regulatory T cells], and by suppressing expression of programmed cell death protein 1 (PD-1) by T cells,” Cascalho and colleagues reported.

C3d vaccination might circumvent the need to identify and target tumor-specific neoantigens. “Free C3d doesn’t require prior knowledge of any specific cancer antigens,” Cascalho explained.

Cascalho disclosed a pending patent application for C3d as an anticancer agent.