Mary Philip, MD, PhD, has been named a 2019 V Scholar and will receive $200,000 from the V Foundation for Cancer Research.
The grant will support her research to develop an organoid model — a miniature cell model of a functioning organ — of the liver. Her goal is to induce cancer into liver organoids, then add T cells and other immune cells to understand how the immune system responds to developing tumors.
This in vitro model will allow three-dimensional observation of immune-cancer interactions at the single-cell level at the earliest stages of cancer development, which is difficult to carry out in mouse models.
The initiative follows a previous study on T cell dysfunction in liver cancer using mouse models by Philip and colleagues that was published May 25, 2017, in Nature. She was the lead author of that study.
“We found that T cells really quickly will get into the liver,” said Philip, assistant professor of Medicine in the Division of Hematology and Oncology and assistant professor of Pathology, Microbiology and Immunology. “They see that something abnormal is going on, but they don’t kill these cancer cells. They become nonfunctional. We saw changes in how DNA gets structured, and it causes these T cells to become less and less responsive to the tumors. We saw that even within four or five days of T cells getting into these pre-malignancies or early malignancies — so even before you get to a full-blown liver cancer — that these T cells were no longer functional.
“That led to the proposal and the work we are starting here, which is to try to understand what is happening in those first few days when the T cells first see these abnormal liver cells that are starting to go through tumori genesis. The ultimate goal is to use this knowledge to make T cells resistant to cancer-induced dysfunction and improve immunotherapy for cancer patients.”
Using organoids for cancer research is relatively new. The first organoid, one built from intestinal stem cells, was developed in the Netherlands in 2009 by Hans Clevers, MD, PhD, and colleagues. Other organoids have been developed in vitro since then, including models for the liver.
“What hasn’t been done yet with the liver is trying to get liver cancer to form in vitro,” Philip said. “So that’s the first thing we’re going to work on, which will be something new. Can we recapitulate in a dish the carcinogenesis that we see in our mouse models? Then the second thing that hasn’t been done is what happens with T cells, looking at T cell interactions with these organoids.”
Philip is a member of the Vanderbilt-Ingram Cancer Center Host Tumor Interactions Research Program.
The V Foundation for Cancer Research was founded by ESPN and college basketball coach and broadcaster Jim Valvano. Since its formation in 1993, the V foundation has awarded more than $200 million in cancer research grants nationwide.