Complement controls the immune synapse and tumors control complement

The synapses between immune cells and their targets are 150 Å wide. They regulate immune cell responses (IRs) to cognate antigens. Here, I outline a potential mechanism for self-nonself discrimination based on the C3d and iC3b proteolytic fragments of complement protein C3. The proposed C3 checkpoint works through complement receptor 3 (CR3), which binds both C3d and iC3b. The CR3 conformations involved differ; the bent, cis-acting CR3 engages C3d, activating the immune cell expressing CR3; the extended, transacting CR3 conformer binds iC3b on another cell, inhibiting IRs. The CR3 complexes formed with iC3b and C3d vary greatly in size. Only bound C3d is small enough to fit within the synapse. It stimulates IRs by countering the inhibitory signals that iC3b generates at the synapse edge. The competition between C3d and iC3b dynamically determines whether or not an immune cell activates. Host cells use regulators of complement activation (RCA) to coat themselves with iC3b, silencing IRs against self by preventing synapse formation. Tumors exploit this process by overexpressing C3 and RCA to masquerade as ‘super-self’, with iC3b masking neoantigens. Enhancing synapse formation by specifically labeling cancer cells as nonself with targeted C3d therapeutics offers a new strategy for boosting tumor-specific immunity.