Enhancing Natural Killer Cell Cytotoxicity Toward Cholangiocarcinoma
Abstract
Despite cholangiocarcinoma (CAC) having one of the highest relative levels of Natural Killer (NK) cell infiltration, little work has been done to investigate the role of NK cells in CAC. The significant infiltration of NK cells into CAC tumors potentially indicates that their function and activation could impact CAC pathogenesis and could be a therapeutic target. Unfortunately, the molecular etiology of CAC is poorly understood, and CAC subtypes are often characterized by their anatomical location: whether they are extra- or intrahepatic, respectively. Given the limited understanding of the genetic drivers of CAC, the standard of care has been restricted to systemic chemotherapy that carries significant toxicities in the elderly population. The lack of targeted therapeutics has resulted in a dismal five-year survival rate of 30% for patients with localized disease and less than 5% for metastatic patients. This research targets both the Biology/Etiology and Therapy Focus Areas of the Rare Cancer Research Program Focus Areas. Cholangiocarcinoma is a rare cancer that typically arises from the epithelial cells lining the bile duct and afflicts about 1.5 in 100,000 Americans yearly. CAC rarely arises in the pediatric and young adult population and has an average age of diagnosis of 70, a patient population that often has significant side effects. The ultimate goal of the project is to identify whether CAC is particularly sensitive to NK cells, which are normally adept at killing cancer cells. The studies described in the research will determine which NK cell receptors are responsible for killing CAC tumor cells. Subsequently, we will determine if high expression of the molecules that bind to the NK activating receptors can increase sensitivity to NK cell killing. Assuming the studies are successful and we can obtain additional funding, it would likely take approximately 5 years for any potential therapy to reach phase 1 studies. The studies proposed within this grant have the potential to generate notable improvements in our understanding of NK cell interaction with CAC. Despite NK cells making up one of the highest relative percentages of immune tumor infiltration compared to other tumor types, relatively little is known about their interactions with CAC tumor cells. Determination of the key NK activation receptors that mediate CAC killing would significantly improve our understanding of CAC and NK cell biology. In addition to directly furthering our understanding of CAC immunobiology, the resulting data from the grant would benefit the NK cell biology field as a whole. These studies supported by the grant would aid future work that would not only seek to explore the role of NK cells in CAC tumor growth in vivo, but also the ability of CAC tumor cells to avoid NK cell cytotoxicity.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310428
Entities
People
- Ian Henrich
Organizations
- Baruch S. Blumberg Institute
- United States Army