Finding a way to STING tumor growth
New function of the immune protein STING -- one that could lead to
improved immunotherapies to treat cancer

Date:
August 24, 2020
Source:
UT Southwestern Medical Center
Summary:
The immune protein STING has long been noted for helping protect
against viruses and tumors by signaling a well-known immune
molecule. Now, scientists have revealed that STING also activates
a separate pathway, one that directly kills tumor-fighting immune
cells.



FULL STORY ==========================================================================
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 Nan Yan, Ph.D., associate professor of immunology and microbiology at UTSW. "We're already pursuing ways to
harness this mechanism to treat tumors." 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 study published last month in the journal 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 Harold C. Simmons Comprehensive Cancer
Center and a Rita C. and William P. Clements, Jr. Scholar in Medical
Research. "We showed otherwise." 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.


========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jianjun Wu, Nicole Dobbs, Kun Yang, Nan Yan. Interferon-Independent
Activities of Mammalian STING Mediate Antiviral Response
and Tumor Immune Evasion. Immunity, 2020; 53 (1): 115 DOI:
10.1016/j.immuni.2020.06.009 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200824105540.htm

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