Immunity is orchestrated by two responses referred to as the innate and adaptive immune systems. Each system works to minimize and clear infections. The innate immune response is a broad-targeting defense network of immune cells that actively survey the body. These cells are the first to signal that something is wrong. Innate immune cells, which comprise of macrophages, neutrophils, eosinophils, basophils, natural killer cells, and mast cells, destroy weaker pathogens and generate a memory response if the body is exposed to that pathogen again in the future. Innate cells also trigger the adaptive immune response to eliminate more resistant infections. Adaptive immunity is specific and stronger in its response. Adaptive immune cells include T and B cells, which specifically bind to surface proteins on infected cells and release cytotoxic molecules that eliminate the infection. Both immune responses work in concert to generate effective immunity and protect the body from disease.
Many medications and treatments work to target the adaptive immune response since these cells are responsible for complete clearance of infected cells. They also have the ability to mount stronger defenses toward hard-to-treat diseases, such as cancer. Specifically, T cells identify and lyse tumors, but become dysregulated due to overstimulation and other pro-tumor molecules. There are two types of T cells: CD8+ T cells and CD4+ T cells. Each plays a specific role in antitumor immunity. CD8+ T cells strictly lyse or destroy cancer, while CD4+ T cells help further activate and coordinate the adaptive immune response. Many cancer therapies are focused on harnessing the T cell response and redirecting the immune system toward cancer. As a result, scientists are working to understand more about T cell biology to enhance and boost T cell-based tumor therapies.
A recent study in Nature Immunology, by Dr. Pavan Reddy and others, demonstrated a new way T cells attack cancer. This new discovery reshapes the way T cell biologist understand immunity and how to effectively target tumors. Reddy is Professor and Director of the Dan L Duncan Comprehensive Cancer Center at the Baylor College of Medicine. His work focuses on tumor immunology and ways to advance cancer treatment. T cells are activated by recognizing proteins expressed by molecules known as major histocompatibility complexes (MHCs). Reddy and his collaborators discovered a previously unrecognized function of MHC molecules in CD4+ T cells.
Researchers used advanced transcriptomic analyses for mouse models and human samples to reveal that CD4+ T cells attack cancer cells once they lose MHCs. They further showed that cancer cells lacking MHC are sensitive to ferroptosis, a form of iron-dependent cell death. This phenomenon was also observed in graft-versus-host disease during bone marrow transplant. The loss of MHC on cancer cells was witnessed in patient samples that were treated with checkpoint inhibitors, a standard T cell activation drug. This work further demonstrates that the absence of MHC enhances CD4+ T cell antitumor function.
Reddy and others have discovered a new role in CD4+ T cell mediated tumor response. This paradigm-shifting discovery has the potential to enhance tumor immunotherapy. New strategies taking advantage of these new findings are currently underway. Scientists hope to leverage this knowledge to enhance both CD8+ and CD4+ T cell therapies. Overall, these data suggest new ways to target solid tumors and improve patient survival.
Study, Nature Immunology, Pavan Reddy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
