Exploring Immunotherapy Resistance in Melanoma and Colon Cancer

A new Duke-led research study reveals groundbreaking insights into the mechanisms behind immunotherapy resistance in melanoma and colon cancer. Nicholas DeVito, MD, a Duke Cancer Institute medical oncologist specializing in gastrointestinal cancer, helped lead the research team in this work.The findings published in Cancer Research focus on the variability in patient responses to immunotherapy and the role of epithelial-mesenchymal transition (EMT) in this process. Despite the benefits of immunotherapy for approximately half of melanoma patients, the underlying mechanisms of resistance remain unclear."Not all patients with melanoma respond to immunotherapy, even though about half of them benefit from it, and most patients with colon cancer do not have a response at all” DeVito said. “Because of that, there's a question of, what is the mechanism behind that?"The team focused this research on the Hedgehog pathway, particularly the transcription factor GLI2, which they found plays a crucial role in immunotherapy resistance. The Hedgehog pathway, typically active during embryonic development, was shown to be associated with invasive and EMT in melanoma.The research revealed that GLI2 regulates two immunosuppressive pathways: the Wnt pathway and the prostaglandin pathway. These pathways are meant to help wounds heal, but tumors use GLI2 to activate pathways that have an immune suppressive influence on the microenvironmentUsing mouse models and patient samples, the team demonstrated that activation of GLI2 in cancer cells leads to immunotherapy resistance. They employed various techniques, including flow cytometry, single cell RNA sequencing, and chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR) to uncover the role of GLI2 in regulating immunosuppressive pathways.These findings suggest that inhibiting specific prostaglandin receptors can prevent immunotherapy escape, and blocking Wnt secretion can restore tumor control after immunotherapy escape, offering potential therapeutic strategies for patients.“If you had a high GLI2 signature in a tumor, there was a more than 75 percent chance that the patient is not going to respond to immunotherapy,” DeVito said. “The drugs that we've used in our mouse studies are all ones that have been used in humans, so they could be easily paired with a GLI2-based biomarker in clinical trials.”By identifying patients with high GLI2 signatures, clinicians can tailor treatments to improve outcomes. This approach is particularly relevant for colon cancer patients, who often exhibit primary resistance to immunotherapy.DeVito hopes to explore the role of GLI2 in colon cancer, particularly in patients with liver metastasis, and further develop biomarkers for combination treatments in this disease. His team is investigating how GLI2-mediated pathways contribute to immunotherapy resistance and spread to the liver by generating an immune-suppressive microenvironment, or ‘home’ for cancer outside the colon. The team is acquiring patient specimens and working with Jatin Roper, MD, assistant professor of medicine in the Duke Department of Medicine, to implement an advanced colon cancer mouse model that better represents human disease.“Immunotherapy is more tolerable and works better and longer than chemotherapy does,” DeVito said. “Using biomarkers, we can have an idea what the molecular pathways driving the immune landscape in the tumor are and can target those pathways in specific patients to improve the effectiveness of existing immunotherapies. Developing the ability to identify which immunosuppressive pathways are active in one tumor and not another also helps us not expose patients without those biomarkers to unnecessary treatments.”

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