Immune checkpoint inhibitors (ICIs) are a type of immunotherapy or cancer treatment that targets specific immune cells known as T cells, which are responsible for eliminating infection. In cancer, T cells express a checkpoint marker, which when bound to another cell surface marker on cancer can inhibit their function. For example, a common checkpoint that inactivates T cell activity includes LAG3. Specifically, the two markers will bind and prevent the T cell from becoming activated and recognizing the tumor. In response to this biological phenomenon, scientists have developed ICIs which block that interaction and allow T cells to properly function. There are many different types of checkpoint markers on T cells that can induce this non-active state when in contact with tumors or other cells in the environment. Unfortunately, this therapy alone is no sufficient in most cancer types to effectively shrink or eliminate tumor growth. Therefore, scientists are developing new therapies that can be paired with ICIs to improve treatment efficacy.
A more recently established form of immunotherapy includes bi-specific T cell engagers (BiTEs). This form of therapy generates antibodies to bring together T cells and cancer. The tumor microenvironment is complex and T cells have trouble locating tumor cells. BiTEs help limit that physical obstacle by possessing binding proteins on both sides of the antibody. Each side either binds to a T cell or cancer cell. As a result, these antibodies can bring cancer cells and T cells together, which allow T cells to eliminate the tumor. BiTEs, in conjunction with ICIs, can elicit robust antitumor immunity and decrease tumor burden. However, scientists are still learning more about checkpoint surface markers that could further enhance therapeutic strategy.
A recent study in Cell, by Dr. Jun Wang and others, demonstrated that the position of LAG3 on the T cell surface is what limits antitumor activity. Previously it was thought that LAG3 binds to another protein on a different cell to inhibit T cell activity. However, Wang and his team discovered that the LAG3 position near the T cell receptor – the protein that specifically recognizes the tumor – prevents T cells from activating. Wang is an Assistant Professor in the Department of Pathology at New York University (NYU) Grossman School of Medicine and Langone Health. His research focuses on improving cancer immunotherapies through ICIs. Specifically, he investigates cell signaling pathways that could improve ICI treatment and more robustly target cancer growth.
Wang and his team are the first to demonstrate that T cell activation is conditionally dependent on the position of LAG3. This challenges the previous literature that states a ligand must bind to LAG3 for inactivation. As a result, this discovery suggests ICI may not work as easily as previously thought. Additionally, researchers realized that this new finding presents an opportunity to improve autoimmune disorders.
Researchers developed a different type of BiTE that inhibits LAG3. This therapy is referred to as a bispecific T cell silencer (BiTS), which targets pathogenic T cells expressing LAG3. Consequently, scientists have found significant therapeutic benefit in various autoimmune disorder through animal modeling. Overall, this work defines a new mechanism that regulates LAG3 and presents a strategy that improves autoimmune disorder treatment.