New approach to block immune inhibitory checkpoint receptor CTLA-4

A recent study has revealed a new way to block CTLA-4, an immune inhibitory checkpoint receptor. The pharmaceutical and research communities already have a significant interest in CTLA-4 because of its potential in fighting cancer. An antibody that blocks CTLA-4, ipilimumab, is already in use for advanced melanoma.

The study, published in Nature Immunology (2014; doi:10.1038/ni.2866), was an international collaboration led by Amnon Altman, PhD, of the La Jolla Institute for Allergy and Immunology in La Jolla, California.

The researchers demonstrated a previously unknown—and pivotal—interaction between an intracellular enzyme protein kinase C-η (PKC-η) and the immune cell receptor CTLA-4. The interaction is critical for the immune suppressive function of regulatory T cells.

Regulatory T cells are a subpopulation of T lymphocytes; however, in contrast to most T cells, they suppress the immune system. This activity is an important component of a healthy immune system, as it serves to dampen exaggerated and potentially harmful immune responses that lead to autoimmune diseases and other inflammatory conditions. Contrary to this effect, regulatory T cells can also produce the undesirable result of inhibiting beneficial immune attacks against cancer.

CTLA-4 is a protein that sits on the surface of regulatory T cells, where it plays an important role in immune suppression. "The way it works is that this enzyme physically binds to the CTLA-4 receptor," said Altman. "This binding is critical for certain suppressive functions of the regulatory T cells to proceed."

Altman and his colleagues showed that binding of the enzyme to CTLA-4 was essential in order for the regulatory T cells to turn down the immune system in mice. Moreover, by eliminating the enzyme in specially bred mice, the research team also demonstrated that "regulatory T cells lacking this enzyme are unable to suppress the immune system's response against a growing tumor," said Altman.

Another key aspect of the study was the finding that, despite the failure of regulatory T cells lacking PKC-η to inhibit an immune response against a growing tumor, these cells retained their ability to inhibit autoimmune disease in a mouse model of inflammatory bowel disease.

"This means that you could potentially create a therapy that would allow for a more effective immune response against cancer without the risk of increasing susceptibility to autoimmune diseases," said Altman. "This is quite desirable because it means the mechanism of action is more specific to tumors as opposed to unleashing an overzealous system-wide immune response that can trigger autoimmune diseases."

Altman explained that this result was possibly due to diverse mechanisms utilized by regulatory T cells to suppress different immune responses.

"At least some of the mechanisms that regulatory T cells use to inhibit autoimmunity seem not to depend on the association between PKC-η and CTLA-4 and, thus, they remain largely operational in regulatory T cells that lack this enzyme," said Altman. "The mechanism we discovered involves a physical contact between regulatory T cells and other critical immune system cells, which may be less important in the autoimmune pathways."

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