Radiation, some chemotherapies and cytotoxic anti-cancer drugs kill tumor cells directly. Immunotherapies, by contrast, rally a patient’s often dormant immune cells to do the job. Prominent among them are T cells, what LJI researcher Michael Croft, Ph.D., calls “the immune system’s warrior cells.”
Croft’s work exemplifies crosstalk between the fields of infectious disease and cancer research, as factors that rally the “troops” in both cases are often quite similar. For example, Croft studies how small signaling molecules or cytokines collectively called tumor necrosis factor superfamily (TNFSF) proteins and their receptors (TNFRSF), which are expressed on T cells, boost the immune system response in paradoxical settings. Drugs that block TNFSF or TNFRSF proteins are being used successfully in the clinic to suppress immune responses to treat multiple autoimmune or inflammatory diseases. Croft’s lab is investigating the other side of that coin: namely whether TNFRSF modulators can enhance T cell responses in the context of cancer.
Regulatory T cells
Several LJI scientists study regulatory T (Treg) cells, a subset of T lymphocytes that dampen excessive immune responses to prevent autoimmune diseases and inflammation. Unfortunately, they can also inhibit immune responses against tumor cells. The laboratory of Amnon Altman, Ph.D., has discovered a novel biochemical pathway involving an enzyme called protein kinase C-eta (PKCh), which is essential for the suppressive function of Treg cells. Treg cells lacking this enzyme were not able to promote tumor growth in mice. Specifically, Dr. Altman is searching for ways to block this enzyme to enhance the body’s immune response against cancer as part of a cancer immunotherapy’s strategy.
LJI’s Hilde Cheroutre, Ph.D., is also searching for ways to rally anti-tumor T cell responses. Working with researchers at Japan’s RIKEN Institute, she has identified a molecular switch that allows so-called T-helper cells to morph into more aggressive killer T cells capable of attacking either tumors or infected cells. These findings could encourage development of potent drugs targeting cancer, AIDS or other infectious diseases.
Finally, LJI’s Stephen Schoenberger, Ph.D., is implementing an immunotherapy strategy that deploys a patient’s own T cells against tumor cells, leaving normal tissues relatively unscathed. The approach is based on the fact that tumor cells exhibit unique mutated proteins on their surface. Schoenberger, partnering with colleagues at UCSD, will employ next-generation DNA sequencing to first identify those “neoantigens” in tumors from patients with head and neck cancer and then isolate pools of patients’ T cells that recognize them. Patients will then be reinfused with their own selected T cells in order to kill cells decorated with the neoantigen. An alternate approach is to create a therapeutic vaccine to stimulate a patient’s immune system to clear cells bearing the marker. Both approaches have proved successful in mice, and trials in humans should begin in mid-2016.