How a checkpoint inhibitor keeps the immune system quiet against cancer

How a checkpoint inhibitor keeps the immune system quiet against cancer

While strong immune responses are needed to help protect the host from infections, the immune system also must curb the magnitude of those responses to limit the damage it can potentially cause. Over the past 8-10 years, a team of researchers have identified some of the molecules that the immune system uses to temper immunity. While these molecules are usually good, they also limit the magnitude of the immune response to cancer. The team has learned that turning off these "brakes" on immunity allows therapeutic response to cancer.

VISTA (V-domain Ig suppressor of T-cell activation) is one of these tempering molecules that negatively regulates immunity. The team describes how VISTA controls immune T-cell responses in their study published in Science.

Unlike all other negative checkpoint regulators (NCRs) that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. Authors report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity.

Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.

"We have learned that keeping your immune system quiet is a challenging and very active process," says the senior author. "VISTA mediates immune system function and its loss can result in the development of unwanted immune responses. But VISTA may also be a valuable target in regulating the immune response in cancer and autoimmunity."

VISTA keeps the immune system's T-cell compartment passive and prevents activation of the immune system to self-antigens such as developing cancer cells. "Like other negative checkpoint regulators, blocking VISTA in cancer may enhance the host's ability to make protective tumor-specific immune responses," says the author.
Currently, there is an antibody specific to VISTA that is going to be used in Phase I clinical trials in cancer to see if it is safe and if it can amplify the immune response to cancer in patients. If so, this antibody may be valuable in the development of drugs and vaccines to provide therapeutic response to cancer and cancer cures.