A study by MD Anderson researchers is shedding new light on how the protein PD-L1 suppresses the immune system, which may help scientists find new ways to identify and treat cancers associated with inflammation earlier.
Led by Mien-Chie Hung, Ph.D., chair of Molecular and Cellular Oncology, the study focused on breast cancer using mice and human tissue samples. The findings may also benefit various inflammation-caused cancers, including lung, colorectal, esophageal, pancreatic, melanoma and liver.
The researcher team’s results demonstrated a previously unknown immunosuppression mechanism in cancer cells by which inhibition of the protein CSN5 activity stopped the ability of PD-L1 to evade the immune system. CSN5 impacted PD-L1’s interaction with PD-1, a cell receptor that prevents T-cell activation when it binds to PD-L1. Many of today’s powerful checkpoint blockade therapies that remove the ability of certain molecules to block the immune are based on this protein pairing.
“Because PD-1 and PD-L1 blockade have yielded such promising clinical effects, understanding the regulatory mechanism of PD-L1 may identify biomarkers and possibly lead to development of new combination therapies,” Hung said.
Also involved in this complex cellular interplay was the cell-signaling protein TNFa, which was shown to play a role in CSN5’s ability to “stabilize” PDL1 and enhance its interaction with PD-1 to allow cancer cells to escape from T-cell killing activity.
“This regulatory event is critical for breast cancer cells to escape immune surveillance via interaction between PD-L1 and PD-1,” Hung said. “Importantly, inhibition of TNFa-mediated PD-L1 stabilization in cancer cells promotes the tumor-infiltrating immune response. Thus, targeting cancer cell PD-L1 stabilization through CSN5 inhibition could help us develop better treatments for cancer accompanied by inflammation.”