Annals of oncology : official journal of the European Society for Medical Oncology
-
Cancers escape immune surveillance via distinct mechanisms that involve central (negative selection within the thymus) or peripheral (lack of costimulation, receipt of death/anergic signals by tumor, immunoregulatory cell populations) immune tolerance. During the 1990s, moderate clinical benefit was seen using several cytokine therapies for a limited number of cancers. Over the past 20 years, extensive research has been performed to understand the role of various components of peripheral immune tolerance, with the co-inhibitory immune checkpoint molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand (PD-L1) being the most well-characterized at preclinical and clinical levels. ⋯ Dual immune checkpoint blockade has demonstrated promising clinical benefit in numerous solid tumor types. This example of concurrent modulation of multiple components of the immune system is currently being investigated in other cancers using various immunomodulatory strategies.