Sending the right signal

A robust immune system is the body’s first line of defence against disease, but what if the immune system behaves like a double agent—as in autoimmune disorders like multiple sclerosis and lupus—attacking pathogens and normal tissue alike? Biochemists at Sunnybrook Research Institute (SRI) have found a way to neutralize the threat of autoimmunity in mice by targeting a molecule on T cells, white blood cells that are the body’s garrison against infection and cancer.

“Often in people who suffer with excessive inflammatory disorders, T cells, instead of [only] attacking foreign antigens, attack ‘self’ antigens—normal proteins and molecules that are expressed by normal tissues. What we’re looking at here is a way of regulating those undesired immune reactions by suppressing the T cells’ activity,” says Aaron Prodeus, a PhD student in the lab of SRI senior scientist Dr. Jean Gariépy.

Under Gariépy’s guidance, Prodeus engineered a molecule called VISTA.COMP that is the first to target the VISTA receptor, an immune checkpoint on T cells, to turn T cells off in preclinical models. Immune checkpoints are junctures on T cells that shut off or limit immune responses to prevent an assault on healthy tissue. Others have deactivated T cells by targeting the VISTA pathway, but only in test tubes; Prodeus and Gariépy are the first to do so in a living organism.

They became interested in the VISTA molecule because it functions similarly to PD-1 and PD-L1, a well-known immune checkpoint pair. PD-1 is a protein on the surface of T cells, and PD-L1 is a molecule expressed by cancer cells that, when it binds to the PD-1 receptor, subdues T cells. Cancer researchers have exploited this discovery by formulating antibodies that block the interaction of PD-1 and PD-L1, thereby freeing T cells to destroy tumour cells. In clinical trials, these drugs, called immune checkpoint inhibitors, have shown promise in treating melanoma, non-small cell lung cancer and kidney cancer, among others.

“That’s the basis of immunotherapy in terms of anti-PD-1 [agents]. That’s fantastic. We can now promote T cell responses to attack cancer. We thought, ‘well, what if we do the opposite—what if we artificially make ligands that instead of blocking these checkpoint receptors can actually stimulate their activity?’” says Prodeus from his office, which overlooks Glendon forest in midtown Toronto. On the large windows next to his desk are notes about his work that he’s written using dry-erase markers. He continues: “Essentially, we’re stimulating an inhibitory signal, and that in turn is going to tell these T cells, ‘slow down,’ and suppress their activity.”

In a study published in JCI Insight, Prodeus and Gariépy examined the effects of VISTA.COMP in mice that received a skin graft that was incompatible with their immune system. In work done with Dr. Reginald Gorczynski, a professor of immunology at the University of Toronto, they found that 15 days after the graft was transplanted, all six of the untreated controls rejected the graft. Strikingly, in the six mice that received injections of VISTA.COMP, all but one of the skin grafts survived 15 days after the transplant. “We treated the mice intravenously with our agent and showed that it allows the graft to grow. When we remove it—bang!—the graft is rejected. So it’s a very potent anti-inflammatory even in an acute setting like [organ] transplantation,” says Gariépy.

In another experiment, they looked at the effect of VISTA.COMP in mice with severe acute inflammation of the liver. They found that the molecule prevented more than one-half of the mice from dying of the illness. “We used these conditions with very acute inflammatory responses, where the impact of our agent would give a black or white answer. In both cases, we saw a dramatic impact,” says Gariépy.

Next, they will study whether VISTA.COMP is helpful in treating other autoimmune disorders, including rheumatoid arthritis, psoriasis and lupus. On the flip side, they also plan to make antibodies and other agents that block the VISTA molecule. These drugs would function as immune checkpoint inhibitors to fight cancer. “VISTA is working in parallel with PD-1. So we think if we block that pathway we might get the immune system to attack the tumour,” says Gariépy.

They have patented VISTA.COMP and are partnering with MaRS Innovation to commercialize their work. The potential for developing a host of therapeutic agents targeting the VISTA pathway is huge, but Prodeus, who defends his PhD near the end of 2017, is taking things one step at a time. “Everything we’ve done is with mouse T cells, mouse models, mouse VISTA. You’ve got to do these things with human tissues, human cells. Obviously we’re not going to inject [it] into humans, but we can use donor cells with human VISTA.COMP and see if we observe in vitro what we see with mouse VISTA. We’ve published a paper, but we’re still at the beginning. I’m trying to figure out where to go from here.”

This research was funded by the Canadian Institutes of Health Research, with infrastructure support from the Canada Foundation for Innovation, and Ministry of Research, Innovation and Science. Aaron Prodeus is supported by a fellowship from the Canadian Breast Cancer Foundation.

Original article: Prodeus A, Abdul-Wahid A, Sparkes A, Fischer NW, Cydzik M, Chiang N, Alwash M, Ferzoco A, Vacaresse N, Julius M, Gorczynski RM, Gariépy J. VISTA.COMP: an engineered checkpoint receptor agonist that potently suppresses T-cell mediated immune responses. JCI Insight. 2017 Sep 21;2(18). pii: 94308. doi: 10.1172/jci.insight.94308.