Researchers at UNC Lineberger Comprehensive Cancer Center have found a possible way to overcome barriers that block effective anti-cancer immune responses, thereby opening the potential for more effective immunotherapies in people.
The findings are published in Nature.
An unfavorable immune environment
immediately surrounding a tumor cell is a major obstacle in using immunotherapy
to treat many solid tumors, especially pancreatic and breast cancer, as the
suppressive environment can block immune responses that could be helpful in
attacking a tumor. One protein, the STimulator of INterferon Genes (STING), has
the promise of powerfully provoking multiple parts of the immune system and
breaking established barriers.
Although activating the immune system to
control malignant tumors has revolutionized cancer treatment, a sizable portion
of patients do not respond to immunotherapy treatments. However, new drugs that
target STING have been a high priority for pharmaceutical development yet
clinical trials have revealed significant tumor resistance to STING-directed
drugs,” said UNC Lineberger’s Jenny PY Ting, PhD, the William R. Kenan Professor of Genetics and professor of
microbiology and immunology at the UNC School of Medicine.
“Clinically, to improve the
effectiveness of STING-targeted drugs, we need to more deeply understand how
these drugs influence different immune cells in the tumor because the
beneficial effects of STING on immunity may be outweighed by its unintended
immune-suppressive effect,” said Ting, the paper’s co-corresponding author and
director of the Center for Translational Immunology at UNC.
The investigators primarily focused on
pre-clinical models of pancreatic cancer as the disease has a five-year
survival rate of only 10% in people and there are few treatment options. They
also expanded the study to other solid tumors, including melanoma,
triple-negative breast cancer and lung cancer. Importantly, what they observed
in pancreatic cancer is broadly applicable to these additional cancers.
In their studies, the researchers made
the surprising finding that activators of STING increased the number of
regulatory B cells, a type of a white blood cell. Regulatory B cells suppress,
rather than increase, anti-cancer immunity and thus would be a hindrance in
tumor immunotherapy. They further showed that these cells secrete
interleukin-35 (IL-35), an immunosuppressive molecule that impairs anti-tumor
immunity. STING-activated IL-35 production in regulatory B cells was also found
in B lymphocytes from pancreatic cancer patients, underscoring the potential
relevance of these findings to humans. In mouse models, by pairing drugs that
activate STING along with antibodies that block IL-35, the researchers achieved
a significant reduction of tumor growth compared to using just a STING
activator or IL-35 antibody alone.
“IL-35 production can result in
multiprong immunosuppression which is a hallmark of treatment-resistant
cancers, such as pancreatic cancer. Our study revealed that activation of STING
can be one such trigger,” said Yuliya Pylayeva-Gupta, PhD, an associate professor of genetics and
co-corresponding author.
The study further showed that the main
route by which IL-35 impedes anti-tumor response is by suppressing the growth
of natural killer cells, which are immune cells that can kill tumor cells.
“Previous research indicated that a STING-triggered response may be critical
for anti-tumor natural killer cell function,” said Sirui Li, PhD, a post-doc in
Ting’s lab at UNC Lineberger and co-first author of the article. “But our
finding provides a previously unappreciated counter-scenario whereby a STING
activator induces B regulatory cells to secrete IL-35, which reduces the number
of natural killer cells, thereby suppressing an anti-tumor response.”
“IL-35 dictates the STING-triggered
response and maintains the critical balance between pro-tumor B cells and
anti-tumor natural killer cell responses,” said Bhalchandra Mirlekar, PhD, a
co-first author and former postdoc in Pylayeva-Gupta’s lab.
The researchers have submitted a patent application for the dual therapy. Their next steps are to clarify if the experimental combination therapy targeting STING and IL-35 will benefit people.
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