Targeting Hepatocyte-Derived Factors to Improve the Efficacy of Immunotherapy in Pancreatic Cancer
Abstract
Pancreatic cancer (PDAC) is the third leading cause of cancer deaths in the United States and its incidence is rising annually. PDAC displays remarkable resistance to immunotherapy. However, the precise reason for this observation is poorly understood. Notably, cancer cell spread to the liver (also called metastasis) associates with decreased likelihood for response to immunotherapy in patients with other types of cancer. In this regard, the liver is well recognized for its important role in educating the immune system to be tolerant to normal proteins present in the body. We hypothesize that the liver is instructed by PDAC to coordinate immune tolerance, which reduces the susceptibility of PDAC to immunotherapy and increases the risk of metastasis to the liver. In this project, our scientific objectives are to determine how the liver shapes immune tolerance in PDAC and to identify and develop novel treatment strategies to intervene on the liver as an approach to improve the efficacy of immunotherapy and to reduce the risk of liver metastasis. The idea that the liver can be a therapeutic target for preventing metastasis and for reversing resistance to immunotherapy is innovative. Strikingly, there are currently no Food and Drug Administration-approved treatments for intervening on metastasis, and the role of the liver in regulating immunotherapy in PDAC is unknown. Our proposal addresses three PCARP Focus Areas: (i) new drug development targeted toward cancer sensitivity and resistance mechanisms, including (i) immune mechanisms of resistance; (ii) development of pharmacological, immunological, or genetic interception approaches; and (iii) understanding the events that promote pancreatic cancer metastasis. In the short term, findings from this project will advance our understanding of the liver as a therapeutic target for improving immunotherapy and reducing metastasis in PDAC. In the long term, findings are expected to guide the development of clinical studies aimed at targeting the liver for clinical benefit in patients with PDAC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110622
Entities
People
- Meredith Stone
Organizations
- United States Army
- University of Pennsylvania