Pancreatic cancer is an almost universally deadly disease that has few effective treatments. Immunotherapy has been hailed as a modern cancer breakthrough since it can use a patient's own immune system to kill cancers anywhere in the body. Unfortunately, pancreatic cancer does not appear to have any measurable response to any known immunotherapy. One way that pancreatic cancer evades the immune system is through the biology of low oxygen, or hypoxia. As pancreatic cancer grows, it develops thick scar tissue that cuts off the blood supply to the tumor, making it hypoxic. Specialized cells called cancer-associated fibroblasts grow in this hypoxic scar and produce substances that allow the c...

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Pancreatic cancer is an almost universally deadly disease that has few effective treatments. Immunotherapy has been hailed as a modern cancer breakthrough since it can use a patient's own immune system to kill cancers anywhere in the body. Unfortunately, pancreatic cancer does not appear to have any measurable response to any known immunotherapy. One way that pancreatic cancer evades the immune system is through the biology of low oxygen, or hypoxia. As pancreatic cancer grows, it develops thick scar tissue that cuts off the blood supply to the tumor, making it hypoxic. Specialized cells called cancer-associated fibroblasts grow in this hypoxic scar and produce substances that allow the cancer to block the immune system. We show that the key to reversing this immunosuppression in pancreatic cancer is to understand how cancer-associated fibroblasts communicate with the immune system. We discovered that cancer-associated fibroblasts need a molecule called hypoxia inducible factor-2 (HIF2) to block the function of cancer-killing immune cells. We also show that inhibiting HIF2 with an FDA-approved drug improves immune responses and doubles the lifespan of mice with pancreatic cancer. This grant seeks to better understand how HIF2 affects immune responses and how to translate this discovery to patients with pancreatic cancer. We will study the mechanisms of how cancer-associated fibroblasts recruit immunosuppressive macrophages and immune cells and identify the specific molecular signals that the cancer-associated fibroblasts use to block the immune system. In addition, we will repurpose a HIF2 inhibitor being used to treat kidney cancer and evaluate its efficacy against pancreatic cancer when used alone or in combination with immunotherapy. Our proposal has potential to improve the lives of patients with pancreatic cancer not only in Texas, but the United States and around the world.

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