Immunotherapy of cancer without induction of autoimmunity - CD6 as a therapeutic target

The CD6 cell surface glycoprotein is expressed by almost all T cells, a small subset of B cells and a substantial proportion of human natural killer (NK) cells. CD6 has multiple ligands and multiple functional epitopes. It is a component of the immunological synapse, and can positively or negatively influence signal transduction in T cells through complex interactions with multiple kinases and adapter molecules. Antibodies to CD6 are effective in the treatment of autoimmune diseases in experimental systems and in humans. The recent discovery that CD318 (CDCP1), a driver molecule in many cancers, is a ligand for CD6 has prompted investigation of CD6 as a possible new target for immunotherapy of cancer. A monoclonal antibody to CD6 rapidly internalizes CD6 and alters gene expression in CD8+ T cells and NK cells to augment the cytotoxicity of human lymphocytes to human cancer cells from a range of neoplasms. This review, using a question and answer format, describes recent work on anti-CD6 as a candidate immunotherapy for cancer as well as relevant advances in our understanding of other aspects of the biology of CD6, and explores the possibility that this approach could avoid the autoimmune complications that are encountered with checkpoint inhibitor treatment of cancer.