Research reveals process used by tumors to induce immunosuppressive cells and evade immunotherapy

Cleveland Clinic researchers recently published a study in Cell Reports which sheds new light on a next-generation immunotherapy target: the immune checkpoint protein VISTA.

Li Lily Wang, Ph.D., and a research team have discovered a new actionable pathway for VISTA, which researchers say helps tumors develop “regulatory immune cells” called myeloid suppressor cells (MDSCs). MDSCs prevent the functioning of other immune cells that attack tumors, such as T cells. Since the discovery of VISTA in 2011, researchers have wondered exactly how the protein promotes the development of MDSCs.

The hypothesis was that the regulatory function of VISTA was linked to its ability to interact directly with T cells and decrease their ability to fight diseases such as infections and cancer. Dr. Wang’s study proved that VISTA – and therefore resistance to immunotherapy – operates along a completely different pathway.

Immunotherapies train the immune system to fight cancer, but proteins like VISTA can get in the way. Co-first author Amin Zakeri, Ph.D., explains that VISTA is an important “immune checkpoint protein” that poses a major barrier to immunotherapies because it prevents our immune cells from responding properly to treatment.

Under healthy conditions, VISTA controls the immune system and prevents attacks on healthy cells. However, in cases of cancer, VISTA may do its job too well and prevent the body from effectively fighting a tumor.

“Immunotherapies allow doctors to treat and manage cancers that could not previously be treated with chemotherapy or radiotherapy with a success rate of 20 to 30%,” explains Dr. Wang of the Department of Translational Research in Hematology and Oncology. from the Cleveland Clinic. “This is incredible progress, but to help the 70 to 80 percent of patients who do not respond to this treatment, we need to understand how tumors can evade the immune system.”

The investigation of VISTA and MDSCs was led by three co-first authors: Dr. Zakeri, Keman Zhang, Ph.D. and Tyler Alban, Ph.D. The team showed that blocking VISTA in models preclinical studies reduced tumor size and increased the ability to respond to immunotherapy. They then took their study further to find out exactly how this response could occur.

“VISTA is involved in multiple pathways and functions in different ways, so we expected to better understand already known pathways through our mechanistic studies,” says Dr. Zhang, a research associate in Dr. Wang’s lab. “Imagine our surprise when we discovered a completely new mechanism.”

In the newly discovered pathway, VISTA is part of a feedback loop that promotes the activation of a gene called STAT3 (which codes for a protein of the same name) and the production of metabolites called polyamines. Polyamines help cells grow, function and replicate, but during cancer they can accumulate and induce the development of tumor-associated MDSC, which helps the tumor resist immunotherapy.

The biomedical research community has focused on the use of STAT3 inhibitors as polyamine-blocking therapeutic treatments, with limited success.

“STAT3 is a very attractive drug target for immunotherapy, but so far, potential drug candidates that inhibit it have largely failed to make an impact due to their toxicity,” says Dr. Wang . “Our data increase the potential to indirectly influence STAT3 and polyamine production by targeting VISTA instead.”

Toxicity in other tissues is not as concerning because the VISTA protein is disproportionately enriched in tumor-associated MDSCs, Dr. Wang added.

These implications are particularly interesting because STAT3 has already been studied extensively, says Dr. Alban. Dr. Alban works as a postdoctoral researcher at the Center for Immunotherapy & Precision Immuno-Oncology at the Cleveland Clinic. Connecting VISTA to a “known agent” like STAT3 will greatly facilitate follow-up studies and drug development, says Dr. Alban, because scientists’ abilities to make therapeutics are limited by their knowledge of the molecule they wish to target. .

Research is currently underway to exploit the connection between STAT3 and VISTA in the search for an effective drug candidate. Dr. Wang says his team’s study has high translational impact across several human cancers, already linking VISTA expression to lower survival outcomes in endometrial cancer.

The team is developing the methods needed to determine which other types of cancer use this mechanism in humans.

“There are many new collaborations and projects in the work to explore the mechanisms behind VISTA and its contribution to the tumor microenvironment,” says Dr. Zakeri. “VISTA has opened many new windows for immune system and cancer research.”