Scientists have used artificial intelligence in an extensive analysis of the immune and genetic landscapes of pancreatic neuroendocrine tumors. Their findings were published by Young et al in the journal Gut.
Pancreatic neuroendocrine cancer starts in cells that produce hormones such as insulin. Once the cancer becomes metastatic, only one in four patients will survive for more than 5 years, and new treatment options are needed.
The new study found that a particularly aggressive type of these tumors can evade immune attack by hijacking the immune system’s response to viral infections, and revealed possible targets for immunotherapy for this rare, hard-to-treat form of pancreatic cancer.
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Genetic Analysis
Scientists used artificial intelligence and genetic analysis to study 207 tumor samples from patients with pancreatic neuroendocrine tumors for the levels of 600 immune-related genes.
Comparing four distinct forms of the disease, they found that samples of the most aggressive form—known as metastasis-like primary tumors—saw changes in activity of 74 immune-related genes, compared with changes in only 12 immune system genes in the more benign insulinoma-like tumors.
The scientists found that 83% of aggressive, metastasis-like primary tumors contained particularly high levels of a gene called TLR3, part of a damage-alert system that mimics the infection response triggered by viruses, drawing immune cells to the tumor. This damage response is related to a form of programmed cell death that occurs when there’s not enough oxygen, which can happen inside metastasis-like tumors, which tend to be larger in size.
The researchers believe that by hijacking the damage response through TLR3, cancer cells can escape from the immune system, leading to the tumor’s ability to grow and evolve.
Possible Immunotherapy Targets
The team also studied the presence of known targets for existing immunotherapies in all four kinds of pancreatic neuroendocrine tumors. They found that the most aggressive type had the highest levels of PD-L1, which suggests they can be targeted checkpoint inhibitors.
The researchers now hope their results will lead to clinical trials to test the benefit of immunotherapies, either alone or in combination with other treatments, for patients with the metastasis-like form of pancreatic neuroendocrine tumors.
Commentary
“Our new study offers an important basis from which to start developing new treatment strategies for a rare form of cancer, which starts in the hormone-producing cells of the pancreas,” said senior study author Anguraj Sadanandam, PhD, Team Leader in Systems and Precision Cancer Medicine at The Institute of Cancer Research, London.
“We found that there is a complex interplay between cancer and immune cells in the most aggressive type of pancreatic neuroendocrine tumors, which suggests immunotherapy could work for patients with this form of the disease,” he continued.
“Our findings could help to pick out those patients most likely to benefit from immunotherapy—and we’re keen to translate our work into clinical trials to test the benefit of different immunotherapeutic strategies to tackle this hard-to-treat form of pancreatic cancer,” he said.
Disclosure: The study was funded by the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research (ICR), the ICR itself, and by Italian charities including the AIRC Foundation for Cancer Research. For full disclosures of the study authors, visit gut.bmj.com.
