Timeframe: 2023 – 2025
Goals: Identifying factors in the tumor environment that impair immune responses to FLC and defining potentially effective immunotherapy strategies
Principal Investigators: Venu Pillarisetty, MD (University of Washington); and Kevin Barry, PhD (Fred Hutchinson Cancer Center)
Study overview: Immunotherapy – harnessing patients’ immune systems to attack tumor cells – has become established as an exceptionally promising approach in cancer treatment. However, the few published studies of FLC to date have showed limited success of currently approved immunotherapies, such as immune checkpoint inhibitors. More promising results in FLC have been seen in (as of yet) unpublished laboratory tests and a clinical trial of a peptide vaccine targeting the cancer’s unique molecular driver. However, among patients who developed a strong immune response against the FLC driver, only a subset showed marked clinical benefit.
Prior work from Dr. Pillarisetty revealed characteristics of immune cells in the tumor environment indicating that their ability to find and kill cancer cells is suppressed in FLC. The main goal of the proposed research is to better understand factors responsible for this suppression, and to find ways to overcome the barriers and thereby fully unleash the therapeutic potential of immune cells against FLC. Certain classes of T lymphocytes, including some capable of directly killing cancer cells, are found within human FLC tumors. However, these immune cells are sequestered away from cancer cells. Second, receptors on T cells do not multiply as much as in other tumor types suggesting the immune system is not responding normally to immune triggers called antigens. Third, cytotoxic T cells—immune cells that can kill cancer cells—are dysfunctional. However, blocking key elements in immune pathways increases immune cell access to cancer cells, reinvigorates T cell antitumor activity, and enhances immune-mediated killing of cancer cells.
This project aim is to investigate how immunotherapy alters these attributes and thus may be employed to reverse the immunosuppression in FLC. The team will characterize the distribution of immune cells in relation to cancer cells and evaluate the proliferation of specific T cells after immunotherapy. They will use slices of FLC tumors from patients to test how combinations of immunotherapy influence the cancer-killing function of T cells. This work will focus on the roles of members of two broad classes of signaling molecules in the tumor microenvironment, known as cytokines and chemokines. These are secreted proteins that regulate inflammatory responses (cytokines) and control cell migration (chemokines). Finally, as an important resource for the field, they will develop a novel mouse model of FLC with an intact immune system to make studying the disease easier.
The ultimate goal is to learn how to create immune system treatments that can prolong patient survival or even cure FLC.