A study in the Journal of Clinical Investigation Insight reveals new functions of free C3d, a fragment of the protein C3 (complement component 3). The finding extends our understanding of the complement system. C3 belongs to the complement system, an integral part of the immune system that increases the ability of antibodies and phagocytic cells to clear pathogens. Complements are generally synthesized in the liver and normally circulate as inactive precursors in the blood. C3d is a fragment of the C3 protein. Scientists previously thought that C3d has no function. However, the new study, led by the University of Michigan, UCLA, The University of Georgia, and Harvard Medical School, shows that free C3d enhances anti-tumor response, which highlights the potential of C3d as a therapeutic agent for cancer. Jeffrey L. Platt is the first author, and Marilia Cascalho is the lead author. The immune system, the body's watchdog, is able to detect and destroy abnormal cells, preventing the development of cancer. However, sometimes cancer manages to evade the immune system. Although it is known that tumors can escape immune surveillance by engaging T cell checkpoint regulators and expanding Tregs, the underlying molecular mechanism remains elusive. The new study reports that free C3d in tumor cells recruits, accelerates, and amplifies anti-tumor T cell responses, which in turn reverses and even prevents tumor growth. C3d works by elevating tumor infiltrating CD8+ lymphocytes, by depleting Tregs, and by inhibiting the expression of PD-1 by T cells. These previously unknown properties of free C3d indicate that it may be used as a cancer therapy or a cancer vaccine. The researchers unexpectedly found that the presence of C3d in living tumor cells or in a killed tumor cell vaccine vitiated restraints on immune surveillance, leading to a rapid control of cancer in mice. These findings suggest that C3d could have an important role in the governance of protective cellular immunity. The researchers made these discoveries when they were testing a vaccine designed to induce the production of broadly neutralizing antibodies against HIV. (Cusabio offers complement related proteins and antibodies as well as Recombinant DRD1.)