Inhibitors against PD-1 and CTLA-4 have become well-established anti-cancer treatments. Now, a research team led by Dartmouth College suggests another immune checkpoint, which acts as a “brake” on immune response, could also serve as a therapeutic target for cancer and autoimmune diseases.
The molecule is called V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA). Unlike other checkpoint regulators that are expressed on activated T cells, VISTA is present on naïve T cells, maintaining their dormancy and tolerance of self-antigens, the team reported in a study published in Science.
Previous studies have shown that mice deficient in VISTA could develop high levels of memory CD4+ T cells and increased cytokine production that led to autoimmunity.
The Dartmouth-led team showed that expression of VISTA by T cells acts as a brake to limit naive T-cell activation. Using single-cell RNA sequencing to compare VISTA-deleted mice with wild-type controls, the researchers found normal mice has higher expression of transcription factors such as Klf2 and Klf6 that are known to be critical for either maintaining T cells in a silence state or inhibiting their proliferation.
In mouse models with graft-versus-host disease, the scientists used VISTA agonists and found the antibodies can suppress the development of the inflammatory disorder by promoting peripheral T-cell death.
Self-antigens may come in the forms of cancer cells or other tissues that are hyperactively aimed by the immune system. So, the researchers suggest, VISTA represents a novel checkpoint regulator that can be targeted by both agonists and antagonists to trigger opposing therapeutic T-cell effects in these two sets of disease.
One company is already developing VISTA-targeting drugs. ImmuNext had originally teamed up with Johnson & Johnson on anti-VISTA antibody JNJ-61610588, but the Big Pharma returned the rights for what it called “business reasons" after a phase 1 study saw one patient experience side effects related to cytokine release syndrome. The small New Hampshire-based biotech has just found a new partner in Curis, which rebrands the compound as CI-8993 for the treatment of cancer and plans to reenter the clinic this year.
Separately, rather than dampening VISTA’s immune-suppressing effect to enhance the body’s anti-tumor responses, ImmuNext in 2016 penned an exclusive deal with Swiss cancer major Roche for developing agonists that amplify VISTA to manage inflammatory diseases.
“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,” Randolph Noelle, Ph.D., the new study’s senior author, said in a statement.
While the study has shed light on VISTA’s role on regulating naive T-cell quiescence, further studies are needed to understand the upstream networks that control the expression of VISTA, the researchers said in the paper.