Immunotherapies have rapidly progressed in the last decade. The idea of directing the immune system toward a disease has become an effective tool for treatment. In every form of immunotherapy physicians use different methods to activate the immune system to identify and target invading pathogens, including cancer. Immune cells are then triggered to rid the body of disease based on infected cell surface markers or neoantigens that signify ‘danger’ to the immune system.
Scientists are continually working to understand the immune system in depth to create stronger and more efficacious therapeutic treatments. Various immunotherapies focus on different immune cells to combat disease. In many cases, the disease dictates the therapy needed. Since the immune system is comprised of various cell types, scientists focus on critical populations that are responsible for targeting disease, including T cells. The main role of T cells is to find and destroy infected cells in the body. Consequently, a lot of immunotherapies target T cells or use T cell function as a readout to determine effective immune response.
While immunotherapies have advanced the field of medicine, there is still a lot that is unclear. In addition, there are different subtypes of T cells with various functions that orchestrate an effective immune response. These different subsets work together to activate other immune cells and target infected cells directly. However, some of these T cells are known to impede immune response and it is unclear the mechanism by which this occurs.
A recent study in Nature, by Dr. Robert Shreiber and others, demonstrated how a tumor-specific T cell subtype inhibits immune response in cancer. Shreiber is the Andrew M. and Jane M. Bursky Distinguished Professor in the Department of Pathology & Immunology at Washington University School of Medicine in St. Louis. He is best known for his work on “cancer immunoediting”, in which the immune system protects the cancer and promotes tumor progression. His other work focuses on tumor biomarker discovery to therapeutically target cancer.
Schreiber and others used various mouse models to investigate a T cell subset known as type 1 regulatory CD4+ T cells (Tr1 CD4 T cells). In the context of cancer, this cell population is known to suppress the immune system and allow tumor progression. Researchers used a vaccine that specifically targets neoantigens on the tumor to overcome this suppressive characteristic. Interestingly, the amount of peptide the researchers included in the vaccine determined the optimal response against the tumor. In this study, vaccines with high doses of peptide diminished immune response efficacy, compared to low dose peptide vaccines which activated a robust antitumor response. The Tr1 CD4 T cells activated by the high peptide dose vaccine expressed protumor proteins that suppressed the immune system and allowed tumor progression, even in the presence of other immunotherapies. To overcome this protumor population, researchers used an antibody to target the loss of antitumor immune cells. As a result, researchers were able to reverse immunosuppression and overcome the protumor high peptide dose vaccine.
Schreiber and others have, for the first time, demonstrated how the peptide dose of a cancer vaccine is critical in developing a robust antitumor response. Additionally, their work showed how the Tr1 CD4 T cell population promotes tumor growth by eliminating other immune cells. This research is critical, particularly now as more cancer vaccines are being developed to treat patients. The discovery of peptide dose, how Tr1 CD4 T cells inhibit the immune system, and how to overcome these immunosuppressive cells provides a foundational understanding of the relationship between our immune system and cancer. Consequently, it provides information that will improve therapeutic efficacy and improve patient survival.
Study, Nature, Robert Shreiber, Washington University School of Medicine in St. Louis