Discovery helps explain why viruses and cancers evade our immune system— and is a likely target for future treatments!

An exciting discovery was published in The Journal of Clinical Investigation that helps explain how certain viral infections, as well as cancers, evade our immune system. This discussion will go into the weeds a bit, but I’ll try to distill down the most important details.

One of the most important cells in our immune system that finds and destroys abnormal cells (cancerous or infected with viruses) are the T cells. The T cell recognizes the abnormal cell by scanning the major histocompatibility complex (MHC) on the cell surface and detecting abnormal amino acid chains linked to it (brought to the surface from internally digested proteins). After recognizing the amino acid chains as “foreign” (non-self) the T cell can then generate and release TRAIL proteins (Tumor Necrosis Factor-related apoptosis-inducing ligand), which trigger cell death in the affected, harmful cells by binding to death receptors. Yes, they are actually called “death receptors”, as they initiate cell death (through apoptosis or necroptosis).

The researchers found that viral infected and cancer cells are able to generate a shortened version of the TRAIL protein (aptly named “TRAILshort”!) which actually blocks the real TRAIL protein and thereby inhibit cell death (apoptosis) in the affected cell! What’s even more fascinating is that the diseased cells release the TRAILshort proteins as small vesicles, which can then also confer TRAIL resistance to nearby, bystander cells! (which would be beneficial to nearby cancer or virally infected cells, to also help them survive)

The researchers emphasize a profound conclusion in their paper: “Blocking TRAILshort may therefore represent a strategy to restore T cell–mediated immunity in malignancies and chronic infections, while delivery of TRAILshort may represent a strategy to induce tolerance.” (Inducing tolerance would be important for patients receiving organ transplants, where we want to avoid rejection of foreign tissue.)

I’m confident we’ll be hearing more about TRAILshort antibody therapies in the not too distant future! One of the best aspects of reading this type of paper is the hope and excitement it can generate for the future of medicine!