Jessica Sieff | November 1, 2018
Immunotherapy — harnessing T-cells to attack cancer cells in the body — has given hope to patients who endure round after round of treatment, including chemotherapy, to little effect. For all of its promise, however, immunotherapy still benefits only a minority of patients — a reality driving research in the field for ways to improve the relatively new approach.
One method for improving efficacy is the development of bio- and activity-based markers to better predict which patients will respond to immunotherapy and identify why some don’t. In a new study in the Proceedings of the National Academy of Sciences, researchers at the University of Notre Dame studying tumors in prostate cancer models found that nitration of an amino acid can inhibit T-cell activation, thwarting the T-cell’s ability to kill cancer cells.
“People put a lot of hope on immunotherapy, and it has worked well for some patients, but overall the number is still low,” said Xin Lu, John M. and Mary Jo Boler Assistant Professor of Biological Sciences at Notre Dame who studies molecular understanding and immunotherapy of metastatic cancer. “By identifying activity-based markers like this one, we can design approaches that shut down the particular mechanisms that inhibit T-cell activation so immunotherapy can work.”
In the study, Lu and his team explain how highly reactive molecules, called reactive nitrogen species (RNS), produced by myeloid-derived suppressor cells (MDSCs) cause nitration of an amino acid in a lymphocyte-specific protein called tyrosine kinase (LCK), which is crucial for T-cell activation. Nitration is a process to add a special chemical group “nitro” to the amino acid molecule, called tyrosine, in proteins. After this modification, the protein may alter its overall structure thus exhibiting different functions. MDSCs are prevalent in solid tumors that contribute to more than 90 percent of all cancers.
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