When the body’s immune system fights cancer, how does it choose a specific target? Researchers from the Howard Hughes Medical Institute Investigator (HHMI) have spent decades studying the molecular structure of the immune system in an effort to answer this question. In December 2017, they reported a screening method that allowed them to identify which “signals” displayed by cancer cells were being recognized by the immune system, effectively discovering a “cancer beacon.”
"This is going to widen the scope of our understanding for how tumors are recognized," Stanford University School of Medicine Protein Engineer Christopher Garcia says. Understanding how immune cells choose targets has wide-reaching consequences for the treatment of cancers through immunotherapies, and may also be illuminating for the treatment of autoimmune diseases.
Garcia and his colleagues used tumor samples from two colorectal cancer patients to evaluate how tumor-infiltrating lymphocytes (immune cells) detect signals for cancer (molecules called antigens). They searched through millions of antigens for the ones that the T-cell receptors (proteins on the surface of lymphocytes) would recognize.
This team first developed a similar biochemical process to look through millions of antigens in 2014. In this recent method, they isolated and read the DNA sequences of individual lymphocytes from the two patients. They used the specific T-cell receptors to sift through millions of potential antigens, which a press release characterizes as “molecular needles in an enormous haystack.” HHMI Investigator Mark Davis, Postdoctoral Fellow Arnold Han and graduate student Marvin Gee played a central role in reading the immune cells’ DNA and searching through antigens.
Not only were they able to identify the antigens recognized by the T-cell receptors, they found that the T-cell receptors from both patients recognized the same tumor antigen. This is a major discovery because it may empower researchers to engineer T-cell receptors to recognize cancer antigens identified as common.
"We have to find antigens that are shared across multiple different patients so that one treatment can serve many different people," Garcia says. HHMI also posits that a common antigen could be used as a vaccine that would teach the immune system to find and destroy the cancer cells. This ability to identify which antigens activate immune cells could also help researchers who are trying to better understand autoimmune disorders at the cellular level.
Garcia has long been dedicated to exploring how T-cell receptors work. In 1996, he was part of a team that first unlocked the 3D structure of T-cell receptors bound to targets. In 2014, he discovered T-cell receptors were “far more specific for their targets” than previously assumed. Garcia sees this recent advancement in comprehending how the immune system works shows the power of investing “in the most basic discovery science.”
"This is a great example of how starting with the most reductionist approach can lead you to very powerful insights with clinical relevance," he says.
“Antigen Identification for Orphan T-Cell Receptors Expressed on Tumor-Infiltrating Lymphocytes” was published in the journal Cell.