Determining whether a gene involved in cancer’s escape from immune detection harbors unique changes could indicate whether expensive immunotherapy agents would be effective in a patient with cancer. Unique genetic alterations, called structural variations, in the programmed-death ligand 1 (PD-L1) gene cause an increase in the production of the PD-L1 protein. Structural variations that increase PD-L1 allow cancerous cells to escape detection by the immune system.1
“This is the first study to illustrate that a structural abnormality in the 3′ untranslated region of the PD-L1 gene causes an abnormally high production of PD-L1 protein, consequently aiding cancer immune escape,” said Keisuke Kataoka, MD, PhD, assistant professor in the Department of Pathology and Tumor Biology at Kyoto University, Japan, and lead author of this study.
Antibodies inhibiting PD-L1 or its receptor, PD-1, have improved prognoses for many patients with cancer and can have remarkable therapeutic effects even in terminally ill patients. Immunotherapy, however, is very costly. Biomarkers that predict the efficacy of immunotherapy could optimize treatment plans and limit costs.
“We identified PD-L1 structural alterations affecting the 3′ untranslated region of the PD-L1 gene in 27% of patients with adult T-cell leukemia/lymphoma by analyzing next-generation sequencing data,” explained senior author Seishi Ogawa, MD, PhD, professor in the Department of Pathology and Tumor Biology at Kyoto University.
Researchers looked for similar structural changes in sequencing data from 10 210 samples from the Cancer Genome Atlas. Started in 2005, the Cancer Genome Atlas catalogues genetic mutations responsible for cancer and is supervised by the National Cancer Institute.
“Through this analysis, we found that such abnormalities were found in many common cancer types, including malignant lymphoma, as well as stomach and cervical cancers,” said Ogawa.
“We also generated human and mouse cells having a similar structural alteration using the CRISPR-Cas9 genome editing system, and confirmed that these cells actually showed an elevated expression of PD-L1 protein and were able to escape the immune attack.”
An ongoing phase 2 clinical trial at Kagoshima University in Japan could reveal the significance of these structural variations in guiding the administration of immunotherapy.
1. Kataoka K, Shiraishi Y, Takeda Y, et al. Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers [published online May 23, 2016]. Nature. doi:10.1038/nature18294.