Finding a way to STING tumor growth

August 24, 2020

DALLAS - Aug. 24, 2020 - The immune protein STING has long been noted for helping protect against viruses and tumors by signaling a well-known immune molecule. Now, UT Southwestern scientists have revealed that STING also activates a separate pathway, one that directly kills tumor-fighting immune cells. Among other implications, the finding could lead to development of longer-lasting immunotherapies to fight cancer.

"This is a major surprise for the field and really broadens what is known about STING," says study leader
STING was first identified about a decade ago as a protein that can activate the type I interferon (IFN) response in immune cells. The IFN response is a powerful and well-studied immune reaction that the body uses to fight everything from viruses and bacteria to rogue tumor cells. Since STING was found to have antiviral and antitumor properties, and to activate IFN, most researchers assumed the IFN pathway was the primary way STING carried out its immune activities. However, some have hypothesized that STING also has other functions; after all, it is found not only in humans and other mammals, but in ancient single-celled organisms that lived hundreds of million years ago, way before the emergence of IFN.

In this
Immunity, Yan and his colleagues developed a version of STING that can't turn on the IFN response but is otherwise functional. Then, they began testing what STING could do independent of its ability to activate IFN. The first surprise, says Yan, was that mice carrying this engineered version of STING could still protect against herpes simplex virus type 1 (HSV-1) infection. This finding reveals that STING can fight against infection without engaging the IFN response.

"It looks like it was this historical misunderstanding that since STING can activate interferon, that's the only way it's controlling viruses," says Yan, a member of the

STING likely does fight viruses, in part, through its interactions with the IFN pathway, Yan adds. But the important lesson learned here is that IFN is not the only weapon STING has to fight viruses.

When the research team analyzed the immune cells in which STING couldn't signal the IFN pathway, they discovered something else - T cells quickly died when STING was activated. T cells, types of white blood cells, are main components of the adaptive immune system.

When they looked at T cells that were actively responding to a melanoma tumor in mice, Yan's group found that the tumor was producing molecules that signaled STING and, in turn, caused the death of the T cells trying to fight the tumor.

"We know that tumors have a number of ways to fight back against the immune system," says Yan. "The most well-known of these is that they turn off T cells, and that process is what many immunotherapies, such as checkpoint inhibitors, try to target. What we discovered is that tumors are also actively trying to kill T cells using the STING pathway. This reveals another opportunity for checkpoint inhibition immunotherapy."

When the researchers deleted STING from the mice, the animals' immune systems more effectively controlled melanoma tumors and fewer T cells died. Based on the results, Yan hypothesizes that drugs targeting STING could help T cells better fight tumors. In addition, methods of reducing levels of STING either through drugs or genetically engineered T cells could be combined with existing immunotherapies to make them more effective, by allowing T cells to survive for longer in the vicinity of a tumor.

Yan and his colleagues are already studying how drugs that target STING may work against cancer and are trying to better understand the molecules that link STING to T cell death.
Other UTSW researchers who contributed to this study were Jianjun Wu, Nicole Dobbs, and Kun Yang.

This research was supported by the National Institutes of Health (AR067135, AI134877, and AI151708), the Cancer Prevention and Research Institute of Texas (CPRIT; RP180288), and the Burroughs Wellcome Fund.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

UT Southwestern Medical Center

Related Tumors Articles from Brightsurf:

A viable vaccine for tough tumors
While immunotherapies work well for some cancers, others are immune-resistant and condemn patients to the severe side effects of long-term chemo treatment.

Women could conceive after ovarian tumors
Women receiving fertility-sparing surgery for treatment of borderline ovarian tumours were able to have children, a study from Karolinska Institutet in Sweden published in Fertility & Sterility shows.

Attacking tumors from the inside
A new technology that allows researchers to peer inside malignant tumors shows that two experimental drugs can normalize aberrant blood vessels, oxygenation, and other aspects of the tumor microenvironment in non-small cell lung cancer (NSCLC), helping to suppress the tumor's growth and spread, UT Southwestern researchers report.

Directing nanoparticles straight to tumors
Modern anticancer therapies aim to attack tumor cells while sparing healthy tissue.

A solid vaccine for liquid tumors
Acute myeloid leukemia (AML) is a deadly blood cancer that kills most of its victims within five years.

Evolutionarily novel genes work in tumors
A team of scientists from Peter the Great St. Petersburg Polytechnic University studied the evolutionary ages of human genes and identified a new class of them expressed in tumors -- tumor specifically expressed, evolutionarily novel (TSEEN) genes.

Identification of all types of germ cells tumors
Germ cell tumors were considered very heterogeneous and diverse, until recently.

Laser light detects tumors
A team of researchers from Jena presents a groundbreaking new method for the rapid, gentle and reliable detection of tumors with laser light.

Better prognosticating for dogs with mammary tumors
For dogs with mammary tumors, deciding a course of treatment can depend on a variety of factors, some of which may seem to contradict one another.

The evolution of brain tumors
Scientists from the German Cancer Research Center found in a recent study that only three different genetic alterations drive the early development of malignant glioblastomas.

Read More: Tumors News and Tumors Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to