Figure 2

Mechanism of action of monoclonal antibody ipilimumab. Generation of an immune signal requires presentation of tumor antigen by major histocompatibility complex (MHC) class I or II molecules, on an antigen presenting cell (APC) such as dendritic cell. However, T-cell activation and proliferation requires a second signal, typically generated by CD28 antigen. When CD28 antigen on T-cell surface simultaneously binds to costimulatory B7-1/B7- ligand on the antigen presenting cell (APC), T-cell upregulate and translocate CTLA-4 receptor molecules to the surface, which binds B7 with a higher avidity than CD28, leading to suppressor effects, with T-cell inhibition, reduction of interleukin-2 (IL-2) secretion, and prevention of immune response against malignant cell. Ipilimumab blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) receptor, thus prevents such inhibitory effect, and allows T-cell to proliferate and mediate an immune reaction against malignant cells. Other regulatory checkpoints with the potential for modulation include the coinhibitory molecule PD-1, as well as costimulatory molecules such as OX40 and 4-1BB. Abbreviations: APC, antigen presenting cells; CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility antigen; TCR, T-cell receptor. (Courtesy of Annals of New York Academy of Science and Wiley, Hoboken, New Jersey, Publisher) [86].