A Partial View of Immune System Regulators
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The PD-1 receptors and its ligands are among the signals that play a role in the body’s complex immune system.
Adapted from Sharma P. Immune checkpoint strategies (Introduction). Presented at: 2012 ASCO Annual Meeting, Clinical Science Symposium; June 1-5, 2012; Chicago, IL.
Increasing evidence suggests that the ability to outsmart the body’s immune response represents a hallmark of tumor development. As such, researchers have begun to look at ways in which we might be able to reinstate the immune response with targeted agents, essentially indirectly treating cancer by treating the immune system. One particularly promising strategy for doing this is to target so-called immune checkpoints
, which act as the off-switch on the T cells of the immune system.
A first-in-class immunotherapy, ipilimumab (Yervoy), a monoclonal antibody that targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) on the surface of T cells, was granted approval by the FDA in March 2011 for the treatment of melanoma. Now, a new targeted immunotherapy aimed at the programmed death-1 (PD-1) T-cell receptor is causing great excitement, and may prove to be more effective and even safer than ipilimumab.
How Cancer Hijacks PD-1
The immune system has long been postulated to be important in protecting the body against cancer. The theory of immunosurveillance was proposed back in the 1950s, and it suggested that the immune system is able to detect cancerous cells and mount an immune response against them in order to kill them off.
Until 1995, researchers believed that the simple recognition of an antigen was enough to generate an immune response, noted immunotherapy pioneer James P. Allison, PhD, during a presentation at the 2012 American Society of Clinical Oncology (ASCO) annual meeting in June. “We didn’t realize how complex regulation of T-cell responses was,” he said.
That understanding began to change when scientists demonstrated that antigenpresenting cells provide costimulatory signals, which led to the identification of CTLA-4, said Allison. His theory that an antibody to CTLA-4 would “take the brakes off” the immune system resulted in ipilimumab.
Now, scientists have an increasingly complex view of how the immune system operates. It has become clear that cancer cells have, in turn, evolved mechanisms to evade an immune response. One way in which they do this is to hijack the immune system’s own fail-safe mechanisms, which are designed to suppress the immune response at the appropriate time in order to minimize collateral damage to healthy tissue.
These fail-safe mechanisms include immune checkpoints, which are inhibitory signaling pathways that switch off T cells at the correct time. Cancer cells are thought to co-opt these pathways to dampen down the immune response at inappropriate times and allow cancer cells to thrive.
Researchers are using this knowledge to fight back by developing cancer immunotherapies, which aim to treat cancer indirectly by inducing or enhancing cancer-specific immune responses. Since many of the immune checkpoints are regulated by interactions between specific receptor and ligand pairs, monoclonal antibodies can be used to block this interaction and prevent immunosuppression.
The two checkpoint receptors that have received the most attention in recent years are CTLA-4 and PD-1. Success with antibodies targeting CTLA-4 led to the approval of ipilimumab, the first targeted immunotherapy agent. PD-1-targeted agents are now hot on its heels.
Like CTLA-4, PD-1 and its ligands are members of the CD28-B7 family of co-signaling molecules that play important roles throughout all stages of T-cell function. The PD-1 receptor is expressed on the surface of activated T cells and, under normal circumstances, binds to its ligands (PD-L1 and PD-L2) that are expressed on the surface of antigen-presenting cells, such as dendritic cells or macrophages. This interaction sends a signal into the T cell and essentially switches it off. Cancer cells take advantage of this system by driving high levels of expression of PD-L1 on their surface. This allows them to gain control of the PD-1 pathway and switch off T cells expressing PD-1 that may enter the tumor microenvironment, thus suppressing the anticancer immune response.
PD-L1 expression was linked to poor clinical outcomes in a variety of different tumor types, reinforcing the idea that the PD-1 pathway was a key target for cancer manipulation of the immune response. This, in turn, makes it a key target for the development of immunotherapy to induce targeted antitumor responses.