Immunotherapy drugs that utilize the immune system to detect and kill cancer cells have been successful against several cancers, yet they are still only effective in approximately 10 to 30 percent of patients with certain tumor types. UPMC Hillman Cancer Center researchers have recently discovered that selectively targeting a group of immune cells called regulatory T cells (Tregs) within a tumor may be a way to boost the immune system’s anti-cancer response.
Dario Vignali, PhD, Leader of the Hillman Cancer Immunology Program, Frank Dixon Chair in Cancer Immunology, and Professor and Vice Chair of Immunology at the University of Pittsburgh School of Medicine, and his colleagues discovered a few years ago that a surface protein called neuropilin-1 (Nrp1), which is expressed on almost all Tregs that infiltrated mouse tumors, was required to maintain the function, integrity and survival of Tregs within the harsh tumor microenvironment. Thus, Nrp1 on Tregs helps suppress the body’s natural anti-tumor immune response thereby helping the tumor survive. Importantly, blocking or deleting Nrp1 in Tregs in mice only impacted their function in tumors and not in the rest of the body, resulting in tumor eradication without inducing autoimmune or inflammatory disease.
More recent studies led by graduate student Abby Overacre-Delgoffe in Dr. Vignali’s lab, and published in Cell, demonstrated that tumor growth in a genetically modified mouse model in which the Nrp1 gene was deleted in only half the Treg cell population, but not the other half, was dramatically reduced when compared to a normal mouse in which Nrp1 was present in all Tregs. Genomic and cellular analyses revealed that a secreted immune molecule called interferon-gamma (IFNy) prevented the suppressive function of Tregs in the mice, particularly and selectively in the tumor microenvironment.
Using another genetically modified mouse model, they found that the role of IFNy in diminishing Treg function was crucial to the success of immunotherapies targeting the PD1 protein that have been proven to be very effective in patients.