- New research shows how a key immune pathway, the STING pathway, which normally defends the body against viruses and cancer, actually dampens immune responses and helps cancer spread.
- When STING is persistently activated, it leads to desensitization and subsequent signaling rewiring, suppressing prolific anti-tumor immunity and instead promoting cancer metastasis.
- The findings suggest that a biomarker-based approach could help identify which patients might benefit from STING activation and which from STING inhibition.
- The study also sheds light on why STING activators (or agonists) have so far shown limited responses in early phase clinical trials.
- This discovery was revealed through a new computational method called ContactTracing that can predict cell-to-cell interactions and responses to these events in the tumor microenvironment. The approach holds promise for understanding diseases where cooperation between cell types is crucial.
A study led by researchers at Memorial Sloan Kettering Cancer Center (MSK) and Weill Cornell Medicine has uncovered a new relationship between cancer cells and the immune system, showing how cancer can selfishly hijack a normally helpful immune system.
Activation of this important immune pathway, called the STING pathway, typically triggers a strong inflammatory response that protects the body from harmful foreign cells. But long-term activation of the same pathway leads to desensitization and eventually "rewiring" of cell signaling, promoting the spread of cancer, the researchers found.
"You might think it looks like a car alarm," he says.Samuel Bakhoum, MD, PhD, a researcher and radiation oncologist at MSK, and one of the study's two lead authors. “If it sounds weird, it will get your attention. But if it rings all the time, you'll get used to it and tune in."
The findings, which werepublished inNature23 augustushelp explain why drugs to activate STING (known as STING agonists) have not been successful in clinical trials in patients with advanced cancer and suggest, in contradiction, that many patients may actually benefit from drugs that block STING activation (STING inhibitors).
"Millions of dollars have been invested in drugs that activate the STING pathway to fight cancer, and so far they have not shown significant anti-cancer efficacy in clinical trials," says Dr. Bakhum. “In the lab, these drugs showed promise, but ina trial with 47 patientsthere were only two whose cancer showed even a partial response. InAnother trial with more than 100 patients.who combined STING agonists with other immunotherapy, the overall response rate was 10%. So the question that prompted this research was, "Why don't they work, despite holding so much promise in the preclinical setting?"
The team's discoveries were made possible by the development of an innovative computing tool in the lab of the study's other lead author,Ashley Laughney, PhD, assistant professor of physiology and biophysics and a member of the Weill Cornell Medicine Institute for Computational Biomedicine. nicknamedcontact tracingThe approach predicts interactions between cells and also examines how different cells respond to stimuli in growing tumors. By means ofchart interactions in a mandala-like patternthe tool revealed that long-term activation of the STING pathway leads to changes in cell signaling that attract cells that suppress the immune response to the area in and around the tumor.
"This is not just a tool to document whether cell type A might be interacting with cell type B," says Dr. Laughney.who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "We're looking at whether and how these interactions really work.to influencethe cell receiving the signal.
The study was led by a team of four co-authors from the Bakhoum and Laughney labs: postdoctoral fellow Jun Li, PhD, and senior research technician Mercedes Duran, MS, from theLaboratorio Bakhoum; en computationeel wetenschapper Melissa Hubisz, PhD, en tri-institutionele student Computational Biology and Medicine Ethan Earlie, MS, van deLaboratorium Laughney.
When cell division goes haywire
At the center of the research is a phenomenon known as chromosome instability.
“It's a hallmark of cancer, especially advanced cancers, where the normal process of cell division gets messed up," said Dr. Bakhum.whose laboratory is part of MSK's human pathogenesis and oncology program.
If chromosomes are the body's manual, it's like some cells are missing a lot of duplicate and/or missing pages, he explains.
"We knew that chromosome instability is an important factor in the ability of cancer to spread, also known asmetastasessays Dr. Bakhoum. "What we found here is that the immune system plays a central role in this process."
The cooperation between cancer cells and the immune system is made possible by STING
Aprevious collaboration between MSK researchers and Weill Cornell Medicine, which was also published inNatureshowed that the complex chain of events caused by chromosome instability leads to changes in cells that cause cancer metastases.
"That study was done in partially immunocompromised mice," says Dr. Bakhum. "So it was really neither here nor there in terms of understanding the role of the immune system."
To determine the role of the immune system, the new study used mouse models of cancer that had either a fully functioning immune system or a severely weakened immune system. He also looked at tumor cells with high and low levels of chromosome instability, as well as cells that did notstitch 1gene, which produces a protein called STING, which activates an inflammatory response when it detects foreign DNA molecules in the cytoplasm.
"What we found was that the effect was highly dependent on the immune system," says Dr. Bakhoum. "Basically, there is a sinister collaboration between chromosomally unstable cancer cells and immune cells, and that collaboration is made possible by STING."
The results from the mouse cancer models were then validated in healthy cells and tumor samples from human patients.
For example, the researchers treated a simple type of cell known as fibroblast with an agonist for STING (the basis of drugs developed for human patients) and observed a strong initial immune response.
"But by day five, there's basically no immune response," says Dr. Bakhoum. “Cells became desensitized to this pro-inflammatory pathway very quickly, mirroring the response we saw in cancer cells. Instead, the cells began signaling stress response pathways that tempered the immune response, which had the opposite effect."
Delve into complex interactions between cells
The scientists used a technique called single cell sequencing to understand all the different cellular players in and around a tumor (also called a tumor microenvironment). The technique allows detailed analysis of all cell types involved (such as macrophages, T cells, B cells, neutrophils and tumor cells) and the ligands and receptors they express. To communicate, cells normally emit ligands that bind to complementary receptors on the surface of target cells, causing a change in the target cell's behavior. While most methods predict cell-to-cell interactions based solely on the mutual expression of complementary ligand-receptor pairs, the research team focused on whether their interaction actually alters the signal-receiving cell.
"One of our key findings was that changing the level of chromosome instability or STING activation dramatically alters environmental responses in and around the tumor," says Dr. Laughney.
And to understand these impactful interactions between cancer cells and different immune cells, the researchers developed ContactTracing. By design, the tool takes advantage of the variability of real-world biology, with no prior knowledge required.
The method is based on the simple premise that there is inherent biological diversity in every tumor: not all cancer cells will secrete the same binding molecule or ligand. And not all immune cells will express the correct receptor for that ligand, explains Dr. Laughney out.
By comparing cells that interact with cells that don't, the tool gives scientists a clearer picture of what exactly changes the interaction between the two.
"When we look at the effects that elicit a response in the cancer microenvironment, all the ligands of those chromosomally unstable cancer cells were associated with a specific cellular stress response, one that involves STING," he says.
And when the same interactions were examined in the context of low chromosome instability or where STING was depleted from the cancer cells, they triggered a different response: a strong immune response that attacked the cancer cells.
The new ContactTracing method could also help illuminate other areas of biology and disease where cell-to-cell interactions are critical, notes Dr. Laughney up.
Findings suggest therapeutic possibilities
The study results suggest an opportunity to improve treatments for many patients with advanced cancer caused by chromosome instability, says Dr. Bakhum.
"It seems that the reason why activating STING is not very effective in these patients is that most patients' cells are already desensitized due to persistent activation of the pathway due to chromosomal instability," he says. "Counterintuitively, these patients may actually benefit from STING inhibition."
Treatment of study mice with STING inhibitors reduced metastasis caused by chromosome instability in models of melanoma, breast cancer and colorectal cancer.
In addition, by identifying the subgroup of patients whose tumors may still show a strong response to STING activation, physicians could select better candidates for STING agonists, says Dr. Bakhum.
Authors, funding and additional disclosures
Other authors of the study include Julie-Ann Cavallo, Christy Hong, Atif J. Khan, Emanuele Lettera, Simon Powell, Jorge S. Reis-Filho, and Hannah Wen from MSK. Karolina Budre, Matthew Deyell, Erina Kamiya, and Austin A. Varela, of Weill Cornell Medicine. Sarah Bettigole, Jonathan J. Havel, and Bernardo Tavora of Volastra Therapeutics. Eileen E. Parkes and Su M. Phyu, from the University of Oxford. Amit Dipak Amin and Benjamin Izar of Columbia University. And Christopher Garris, of Harvard University.
The study was supported by the National Institutes of Health and the National Cancer Institute (P50CA247749, DP5OD026395, R01CA256188, P30-CA008748, R01CA256188, R01CA280414, R01CA280572, U01CA210152, R21-CA266660, R3 7 CA25 8829, R21CA263381, R01CA280414, R01CA266446, P50CA247749 ); Congressional Medical Research Program (BC201053); the Burroughs Welcome Fund; the Josie Robertson Foundation; the Survival Cycle Fund; a Kellen Junior Faculty Award; the Melanoma Research Alliance; the Lung Cancer Research Foundation; the Pershing Square Sohn Cancer Research Alliance; the Tara Miller Alliance for Melanoma Research; the V Foundation; the Oxford Institute of Radiotherapy; the Prostate Cancer Foundation; the Welcome Fund; the American Society of Clinical Oncology; the Academy of Medical Sciences; the Breast Cancer Research Foundation; a Susan G. Komen Leadership Scholarship; and a grant from the STARR Cancer Consortium.
Dr. Bakhoum holds a patent related to some of the work focusing on chromosome instability and the STING pathway in advanced cancer. He owns stock, is remunerated, serves as an advisor and serves on the Scientific Advisory Board and Board of Directors of Volastra Therapeutics, and is a member of the Scientific Advisory Board of Meliora Therapeutics.
Dr Parkes, Dr. Izard, Dr. like, dr rice filho en dr. GarrisDisclosed links to the pharmaceutical and/or financial sector.Dr. Bettigole, Dr. Havel and Dr. Tavora are employees of Volastra Therapeutics and own equity in the company.