Timeframe: 2016 – 2019
Goal: Study the interactions between the immune system and FLC in a mouse model
Principal Investigator: Kevin Barry, PhD
Study overview: Cancer immunotherapies harness the power of the immune system to kill tumors. Checkpoint blockade immunotherapies are an exciting class of cancer immunotherapies that remove the brakes from the immune system and allow effective killing of tumor cells. These therapies function by targeting molecules that inhibit tumor-directed responses by immune cells called T cells. T cells are important for protecting patients from tumors as these cells directly kill tumor cells and modulate the global immune response towards tumors. Immunotherapies targeting T cells have been remarkably effective in treating non-FLC cancer patients, leading to tumor regression and offering long-term protection, effectively providing a cure to cancer in some patients. However, at the time of this study,very little was known about how the immune system interacts with FLC or if immunotherapy would be an effective treatment for FLC.
The study of the efficacy of immunotherapy in the treatment of FLC is hampered by the fact that the current patient-derived xenograft animal models of FLC utilize the transplantation of human tumor into immune compromised animals. The lack of an effective immune system allows the host mice to grow tumors, but also makes it impossible to study the interactions between the immune system and FLC in this model system. This study harnessed a preclinical mouse model of FLC developed by Dr. Julien Sage and Stanford University with a fully functional immune system to understand how the immune system interacts with FLC. These studies represented the first steps towards treating FLC patients with immunotherapy in the clinic.
Results: The investigator analyzed a mouse model that conditionally expressed the DNAJB-PRKACA fusion protein. While the hepatocytes expressed the fusion protein, there was no tumor development once the mice were aged. This suggested that the expression of fusion protein in hepatocytes may not be sufficient to drive tumorigenesis in FLC.
Additionally, to explore the immune cells present in FLC, the researchers obtained fresh patient samples and dissociated the tumor into a single cell suspension. Those suspensions were sorted into a non-immune fraction, an immune fraction consisting of all immune cells except T cells, and a T cell fraction. The cells were then analyzed to identify the transcriptional makeup of the immune cells in FLC at the single cell level.
The study founds that the T cell population was made up of a large segment of exhausted T cells, which is indicative of a suppressive immune microenvironment and usually reduces the efficacy of immunotherapy approaches. Follow up analysis of the dataset will help to identify unique changes in the genes expressed in the immune cells within FLC and understand the characteristics of how the immune system responds to FLC.
Implications: These studies will help to fully characterize the distinct transcription programs in immune cells in FLC. These studies are critically important to understand the interaction of the immune system with FLC and to design effective immunotherapy approaches.