Tumor development is characterized by the accumulation of mutational and epigenetic changes that transform normal cells and survival pathways into self-sustaining cells capable of untrammeled growth. Although multiple modalities including surgery, radiation, and chemotherapy are available for the treatment of cancer, the benefits conferred are often limited. The immune system is capable of specific, durable, and adaptable responses. However, cancers hijack immune mechanisms such as negative regulatory checkpoints that have evolved to limit inflammatory and immune responses to thwart effective antitumor immunity. The development of monoclonal antibodies against inhibitory receptors expressed by immune cells has produced durable responses in a broad array of advanced malignancies and heralded a new dawn in the cancer armamentarium. However, these remarkable responses are limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Preclinical and clinical studies with immune checkpoint blockade are exploring the therapeutic potential antibody-based therapy targeting multiple inhibitory receptors. In this chapter, we discuss the current understanding of the structure, ligand specificities, function, and signaling activities of various inhibitory receptors. Additionally, we discuss the current development status of various immune checkpoint inhibitors targeting these negative immune receptors and highlight conceptual gaps in knowledge.
Keywords: BTLA; CTLA-4; Immunotherapy; Inhibitory receptors; LAG-3; PD-1; TIGIT; TIM-3; VISTA.