Another possibility for Nature to overcome the barriers of cancer immunotherapy

Researchers at the University of North Carolina's Reinberg Comprehensive Cancer Center have discovered a possible way to overcome obstacles that impede an effective anti-cancer immune response, opening up the potential
for more effective immunotherapies in humans.
The findings were published in the journal
Nature.

The unfavorable immune environment around tumor cells is a major barrier to the use of immunotherapy to treat many solid tumors, especially pancreatic and breast cancers, because suppressing the environment can block the immune response
that helps attack tumors.
Interferon gene stimulating protein (STING) promises to powerfully stimulate multiple parts of the immune system and break down existing barriers
.

"Although activating the immune system to control malignancies has revolutionized cancer treatment, a significant proportion of patients do not respond
to immunotherapy.
However, new drugs targeting STING have always been a high priority for drug development, but clinical trials have shown that tumors are significantly resistant to STING-targeted drugs," said Dr.
Jenny PY Ting of the University of North Carolina at Reinburg, a William R.
Kenan professor of genetics and professor of microbiology and immunology at
the University of North Carolina School of Medicine.

"Clinically, in order to improve the effectiveness of STING-targeted drugs, we need to gain a deeper understanding of how these drugs affect the different immune cells in tumors, because the beneficial effects of STING on immunity may be offset by its unexpected immunosuppressive effects," Ting said
.

The researchers focused on preclinical models of pancreatic cancer because the disease has a 5-year survival rate of only 10 percent in humans and treatment options are few
.
They also extended their research to other solid tumors, including melanoma, triple-negative breast cancer and lung cancer
.
Importantly, the results they observed in pancreatic cancer are broadly applicable to other cancers
.

In their study, the researchers made a surprising discovery that STING's activator increases the number of regulated B cells, a type of white blood cell
.
Regulatory B cells suppress rather than increase anticancer immunity and therefore become an obstacle
to tumor immunotherapy.
They further showed that these cells secrete interleukin-35 (IL-35), an immunosuppressive molecule that impairs anti-tumor immunity
.
The production of IL-35, which regulates STING-activation in B cells, has also been found in B lymphocytes in pancreatic cancer patients, underscoring the potential relevance of these findings
to humans.
In the mouse model, by pairing STING-activating drugs with antibodies that block IL-35, the researchers achieved a significant reduction
in tumor growth compared to using only STING activators or IL-35 antibodies.

"The production of IL-35 can lead to multi-site immunosuppression, which is a feature of drug-resistant cancers, such as pancreatic cancer
.
Our study suggests that the activation of STING could be such a trigger," said
Dr.
Yuliya Pylayeva-Gupta, associate professor of genetics and co-corresponding author.

Research further shows that the main way IL-35 hinders the anti-tumor response is to inhibit the growth of natural killer cells, which are immune cells that can kill tumor cells
.
"Previous research has shown that STING-induced responses may be critical against natural killer cell function in tumors," said Dr.
Sirui Li, a postdoctoral fellow in Ting's lab at the University of North Carolina at Reinburg, who is also a co-first author
of the article.
"But our findings provide a previously underappreciated counter-protocol, namely STING activators that induce B-regulatory cells to secrete IL-35, thereby reducing the number of natural killer cells and thus inhibiting the anti-tumor response
.
"

"IL-35 determines the STING-induced response and maintains a critical balance between pro-tumor B cells and anti-tumor natural killer cell responses," said
former postdoc and co-first author Dr.
Bhalchandra Mirlekar, Ph.
D.
, of the Pylayeva-Gupta lab.

The researchers have filed a patent application for
this dual therapy.
Their next step is to clarify whether experimental combination therapies targeting STING and IL-35 will benefit
people.

STING-induced regulatory B cells compromise NK function in cancer immunity