Despite multi-agent chemotherapy regimens, oncogenomics, precision medicine, and cancer screening programs, the rate of death from cancer in the United States has not changed significantly since the 1950’s. Over the same period of time, the rate of death from heart disease decreased by two-thirds due to medical advances. Current standard-of-care treatments for metastatic solid cancer produce durable complete responses in less than 1% of patients. Dramatic change is needed in our approach to treating metastatic cancer. The Eil Lab focuses on developing new approaches to direct a patient’s own immune system to recognize and destroy cancer cells.
T cells, a type of immune cell that emigrates out of the thymus, can recognize and kill cancer cells. Recent medical advances have led to the development of cancer treatments based on the antitumor activity of T cells (checkpoint blockade and the adoptive transfer of tumor-specific T cells). These revolutionary therapies have produced dramatic clearance of widespread cancer in some patients. However, in most cases while T cells can be found infiltrating cancers, their function is often constrained within tumors – allowing immune evasion and cancer progression.
While the successes achieved with T cell based therapies demonstrate the promise of a new era of cancer treatment, disease progression currently remains the most common outcome owing to tumor-induced immune evasion and T cell dysfunction. To achieve meaningful progress in the application of T cell therapies for solid cancers, two remaining barriers must be overcome. 1) There are limited safe and effective T cell targets that distinguish the cancer from normal tissues. 2) The hostile environment of tumors deploys effective tools to prevent the function of T cells that do recognize cancer cells.
While there remains a critical need to augment T cell antitumor function within cancers, those features of the intratumoral microenvironment that drive immune evasion remain unclear. This topic remains an area of intense investigation, with many investigators focusing on cytokines (TGFβ), co-inhibitory signals (CTLA-4, PDL-1), and cell-cell interactions (regulatory T cells & myeloid derived suppressor cells) as mechanisms of tumor induced immune suppression. However, tissue and biochemical characteristics specific to tumors may also be important for T cell function.
A high abundance of cell death characterizes many tumors and is associated with poor prognosis. Our prior work identified that cancer cell death results in the release of potassium ions (K+; normally sequestered within the cell), into the surrounding tumor milieu thereby increasing the extracellular potassium ([K+]e). We found that the resultant elevation to [K+]e directly suppresses T cell receptor (TCR) induced activation and drives metabolic reprogramming to maintain T cell stemness (Eil R et al., Nature, 2016 & Science, 2019). This prior work was the first demonstration that extracellular K+ is a major determinant of T cell function.
In current efforts the Eil Lab uses genetic engineering strategies with viral (retro and lentiviral transduction) and non-viral (CRISPR-Cas9) techniques, pre-clinical models adoptive T cell transfer for cancer treatment, and human samples to develop new therapies. We aim to immediately translate our findings to patients with metastatic cancers, with an emphasis on those involving the liver and pancreas. As a surgeon-scientist, Dr. Eil has a unique perspective and platform, allowing us to extend our studies to clinical and research specimens as well as prospective clinical trials treating patients with cancers involving the liver, bile ducts, and pancreas.
Work in the Eil Lab is generously supported by
- OHSU School of Medicine
- American Association for Cancer Research
- American Society of Clinical Oncology
- Pancreatic Cancer Action Network
- National Cancer Institute/ NIH
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