Immunotherapies have drastically altered the scope of cancer therapies in the past decade. Immune-based approaches target the immune system, making it better equipped to fight cancer. This mechanism is in contrast to traditional approaches, like chemotherapy and radiation, which act by killing cancer cells but can also damage nearby healthy tissue.
Immunotherapies have proven effective in certain types of cancer, including those referred to as “hot,” characterized by high levels of immune cells and mediators that support anti-tumor immunity. Other cancers characterized as “cold” lack a favorable immune microenvironment and thus often resist immunotherapeutic agents.
One immunotherapy under active investigation in clinical trials targets a molecule called NKG2A/CD94 located on two critical types of anti-cancer immune cells, natural killer (NK) and CD8+ T cells. NKG2A/CD94 represents an immune checkpoint which binds with a ligand called major histocompatibility complex E (MHC-E). Because MHC-E tends to become highly expressed on cancer cells, targeting the interaction between NKG2A /CD94 and MHC-E is being studied for various malignancies, including head and neck squamous and colorectal cancers.
A recent study published in Cell Reports investigated how NKG2A /CD94 blocking agents work in an effort to understand how to make it work more effectively. The application of NKG2A blocking antibodies alone was insufficient to bypass the immune checkpoint and allow anti-tumor immunity. The researchers found that, in mouse models, an inflammatory “signal” was needed, in addition to NKG2A blockade, for anti-cancer activity. Without providing these additional signals, the ligand (called Qa-1 in mice) does not become visible on the cell surface and, thus, renders the blocking agent ineffective.
Further, the researchers identified a molecule (LILRB1) that inhibited MHC-E from activating another set of immune cells, macrophages. Importantly, further investigation of LILRB1 could help researchers understand why immunotherapies work in some patients and not others.
The authors conclude that these findings will help advance immune checkpoint inhibitor therapies by clarifying the framework by which NKG2A/CD94 blockade boosts anti-tumor immunity.
Sources: Front Immunol, Clin Cancer Res, Cell Reports
