Northwestern Medicine scientists have developed a method for identifying reactive cysteines on peptide antigens within the immune system, a development which may prove useful in cancer immunotherapy, according to a study published in Nature Communications.
While it’s known that major histocompatibility complex class I (MHC-I) plays a central role in orchestrating immune responses to cancer, less is known about the reactivity of peptides displayed by MHC-I and how to harness them for potential therapies.
“When cells are infected by viruses or become cancerous, they can present peptides derived from viral or mutant proteins. Our immune system, particularly T-cells, recognizes these abnormal peptides and eliminates the diseased cells,” said Xiaoyu Zhang, PhD, assistant professor of Chemistry and senior author of the study.
In the study, Zhang and his collaborators set out to understand the reactivity of peptide antigens – substances that trigger the body’s immune system to produce antibodies – and explore ways to use the antigens to elicit immune responses.
First, investigators developed molecular probes designed to react with cysteines: protein building blocks found within peptide antigens displayed on the surface of MHC-I molecules.
Next, investigators tested the probes on different human leukemia cell lines and found that the probes reacted with cysteines on several different peptide antigens, producing measurable signals.
Finally, the scientists tested whether the probe could successfully mark leukemia cells, allowing them to be recognized by immune fighter cells. After the probe marked the leukemia cells, it induced a process known as antibody-dependent cellular phagocytosis, which could serve as a potential strategy for triggering cancer cell death.
“This is the major innovation – scientists have never been able to target antigen peptides with small molecules, but we demonstrate the feasibility of this approach,” said Zhang, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
The findings could pave the way for more effective immunotherapy strategies, Zhang said.
“In this study, we also identified several peptide antigens that are more highly expressed in cancer cells compared to normal cells,” Zhang said. “We are currently focusing on these antigens to identify more specific small molecules that can target them. In the future, we aim to harness these specific small molecules for cancer immunotherapy.”
Deyu Fang, PhD, the Hosmer Allen Johnson Professor of Pathology and member of the Lurie Cancer Center, was a co-author of the study.
The study was supported by the Ono Pharma Foundation and National Institutes of Health grant T32 GM149439.
