Pancreatic cancer has one of the lowest survival rates of any cancer and in most cases does not respond to treatment. In the last decade, immunotherapy, therapy that attempts to activate the patient's own immune system to attack the tumor, has reshaped the landscape of cancer care. Effective immunotherapy relies on the immune cells (e.g. T-cells) being able to travel to the tumor, recognize the cancer cells and ultimately kill them. Despite most pancreatic cancer tumors harboring genetic mutations that would allow immune cells to recognize them, immunotherapy has so far not been effective in treating pancreatic cancer. This is believed to result from multiple factors including: (1) the stron...

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Pancreatic cancer has one of the lowest survival rates of any cancer and in most cases does not respond to treatment. In the last decade, immunotherapy, therapy that attempts to activate the patient's own immune system to attack the tumor, has reshaped the landscape of cancer care. Effective immunotherapy relies on the immune cells (e.g. T-cells) being able to travel to the tumor, recognize the cancer cells and ultimately kill them. Despite most pancreatic cancer tumors harboring genetic mutations that would allow immune cells to recognize them, immunotherapy has so far not been effective in treating pancreatic cancer. This is believed to result from multiple factors including: (1) the strongly immune suppressive environment in pancreatic tumors, and (2) the fact that prolonged T-cell activation is associated with the cells losing their ability to kill cancer cells, a process referred to as T-cell exhaustion. In this proposal, we aim to identify factors that enhance the ability of T-cells to localize to the tumor site, resist exhaustion and ultimately kill more cancer cells. To do this, we will use our newly developed platform, which utilizes CRISPR technology to evaluate hundreds of gene at the same time, to find candidates that enhance T-cell activity in pancreatic cancer, focusing on factors that can be targeted with FDA-approved drugs. The results of these "genetic screens" will then be validated using patient-derived tumor and immune cell cultures to find candidates that can be tested in the clinic.

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