T-cell function is tightly regulated in order to prevent inappropriate activation or collateral damage during productive immune responses. One of the critical cell intrinsic regulatory elements is a series of inhibitory cell surface receptors. In normal immune responses, the integration of signaling from the T-cell receptor (signal 1), costimulatory and coinhibitory receptors (signal 2), and further signals provided by cytokines (signal 3) determine cell fate and activation status. Lack of appropriate stimulatory elements or an abundance of inhibitory signals can drive anergy or exhaustion, preventing the immune system from responding to foreign antigens, particularly those presented chronically such as cancer neoantigens. Multiple elements of this rheostatic system are therefore potentially targetable to enhance immunity for therapeutic benefit. Drugs targeting the inhibitory signaling pathway checkpoints (checkpoint inhibitors) have shown efficacy in several human cancers, including hematologic malignancies, forming the basis for the award of the Nobel Prize for Medicine in 2018 to James P. Allison and Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation.” Insights into the pathways most relevant for immune evasion in specific cancers have underpinned significant clinical progress and offer promising areas for future research, often in combination with other therapeutic modalities.
Immune checkpoints represent one of the most promising therapeutic targets for amplifying antitumor immune responses in patients with cancer. They consist of an array of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses. Tumors subvert some of these inhibitory pathways as a major mechanism of immune resistance, particularly to suppress tumor antigen–specific T-cell responses. Although there is an extended array of receptors that exert inhibitory effects, the two that are most advanced in terms of development of targeted therapeutics are cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), or its ligand programmed death-ligand 1 (PD-L1). As cell surface receptors, they lend themselves well to development of antibody-based therapeutics, the immune checkpoint inhibitors (CPIs).
BASIC BIOLOGY OF CTLA-4 AND PD-1
The amplitude, quality, and durability of T-cell responses, which are initiated through antigen recognition by the T-cell receptor (TCR), are regulated by a balance between costimulatory and inhibitory signals. Under normal physiological conditions, immune checkpoints are crucial both for the maintenance of self-tolerance and for the protection of normal tissues from the impact of normal immune responses to pathogens.1 CTLA-4 is a major regulator of the initial priming of immunity. It is expressed by activated CD4+ and CD8+ T cells, although surface expression is tightly regulated with a short half-life, being rapidly mobilized to the immune synapse after TCR engagement.2 It is constitutively expressed by natural and inducible Foxp3+ regulatory T cells (TREG). It shares its ligands (CD80 and CD86) with the classic ‘signal 2’ costimulatory receptor CD28, affecting most of its activity through higher avidity and outcompetition ...