The protein at the center of this study is called programmed-death ligand 1, or PD-L1. The genetic mutation that occurs and promotes cancer growth disrupts normal structure of the gene’s 3’ untranslated region of the gene the codes for the PD-L1 protein. The researchers plan to continue investigating these structural changes to understand how cancer cells can grow uncontrollably with the immune system inhibited by PD-L1 activity.
There are very effective treatment options using antibodies that target either PD-L1 or its receptor, PD-1, that exists on the surface of immune cells like T lymphocytes. However, these therapies are just as expensive as they are effective. In order to create treatment options that are both effective and affordable, the researchers from Kyoto University set out to identify cancer biomarkers to pinpoint which patients would respond especially well to immune checkpoint inhibitor drugs like PD-L1 targeting antibodies.
Of the 27 percent of patients with adult T cell leukemia or lymphoma who had genetic alterations of the 3’ untranslated region of the PD-L1 gene, the researchers used next-generation genetic sequencing data in attempt to identify the source of alteration. The researchers also sequenced data from over ten thousand samples from the Cancer Genome Atlas, finding similar alterations in other cancer types, including malignant lymphoma, stomach cancer, and cervical cancer.
The Cancer Genome Atlas is a collaboration between the National Cancer Institute and the National Human Genome Research Institute dedicated to providing comprehensive maps of key genomic changes in over 30 types of cancer.
The researchers were able to generate the same genetic alterations of the 3’ untranslated region of the PD-L1 gene in human and mouse cells using CRISPR-Cas9, a genome editing system using short palindromic repeats that target DNA based on sequence complementarity. Just like their previous findings, these cells had an elevated level of PD-L1 expression, and cancer cells were able to evade an immune attack.
On tap next for this research group is to test the structural genetic alteration as a genetic marker for cancer in a phase II clinical trial.
“Once we confirm the significance of these genetic alterations, it’ll be a game changer for immunotherapy in cancer,” said senior author of the study, Seishi Ogawa, PhD.
Sources: Kyoto University, New England Biolabs, Nature, Cancer Genome Atlas