Transgenic T-cell Receptor Expression Is Suppressed Epigenetically

Researchers at UCLA's Jonsson Comprehensive Cancer Center have identified a phenomenon in which cancer patients receiving adoptive cell therapy immune treatments display decreased expression of transgenic T-cell receptors (TCR) over time, even when it is present at the DNA level. As a result, the team observed that structural changes to the DNA via DNA methylation make it impossible for transcription and translation to occur—a crucial step in the flow of genetic information from DNA to RNA. Their results were published in Cancer Discovery.  

Adoptive cell therapy treatments are known to have positive initial response rates but frequent relapse. Decreased response to immunotherapeutic treatments usually occurs in the setting of poor long-term persistence of cells expressing the transgenic TCR. "The issue is this phenomenon happens over time," says lead author Theodore Scott Nowicki. 

After analyzing 16 clinical transgenic adoptive cell therapy samples taken before treatment from patients with sarcoma and melanoma, they observed patterns of expression of transgenic TCR at the DNA and protein level. Their results showed that patients with the greatest expression suppression also displayed significant increases in DNA methylation within the murine stem cell virus (MSCV) y-retroviral vectors.

The team aims to use their knowledge to help in the development and design of viral-vector gene engineered adoptive cell transfer therapies. "We're hoping this can help inform the design of future generations of these types of therapies and pinpoint different vectors that might be more or less vulnerable to this phenomenon," Nowicki adds.