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Structural Variant in PD-L1 Regulatory Region Helps Some Cancers Dodge Immune System

NEW YORK (GenomeWeb) – Structural changes affecting the regulation of the PD-L1 gene appear to help some cancers dodge the immune system, according to a new study in Nature.

A Kyoto University-led team used genome and/or RNA sequence data for more than four-dozen adult T-cell leukemia/lymphoma cases to search for non-coding structural variant clusters, uncovering structural variants in the 3' untranslated region of the PD-L1 that appeared to amplify the gene's expression, apparently contributing to tumors' ability to evade the immune system.

Similar structural variant patterns turned up in samples from individuals with diffuse large B-cell lymphoma and stomach adenocarcinoma, as well, the researchers reported. And their follow-up experiments in a mouse model indicated that such 3'-UTR alterations can boost PD-L1 expression, prompting tumor protection from the immune system.

"Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3'-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumor immunity through PD-L1 over-expression," senior author Seishi Ogawa, a pathology and tumor biology researcher at Kyoto University's Graduate School of Medicine, and his co-authors wrote.

Past studies suggest enhanced expression of the programmed cell death protein PD-1 or the PD-L1 ligand it binds help tumors dial down immune system mechanisms that might otherwise impede cancer growth.

For the latest analysis, the researchers did genome sequencing on samples from 49 individuals with adult T-cell leukemia/lymphoma, searching for suspicious gains, losses, translocation, inversions, tandem duplications, and so on. All but six of the samples were also assessed by RNA sequencing.

The team's structural variant detection approach revealed that 13 of the adult T-cell leukemia/lymphoma samples tested — more than one-quarter — contained structural variants affecting a site on chromosome 9 that falls in the 3'-UTR of PD-L1.

The alterations appeared to truncate the gene's 3'-UTR and/or rearrange the gene's open reading frame, enhancing PD-L1's expression and stability.

When they expanded their search for similar structural variants in other cancer types—using data from the Cancer Genome Atlas to assess samples from 10,210 individuals with 33 cancer types — the researchers uncovered still more examples of the expression-boosting regulatory changes affecting PD-L1.

For example, the team tracked down PD-L1 transcripts with truncated 3'-UTRs in four of the 48 diffuse large B-cell lymphomas and in nine of the 415 stomach adenocarcinoma cases considered. It also saw examples of tumor-associated human papillomavirus or Epstein-Barr virus sequences that had integrated at the PD-L1 locus in samples in cervical, head and neck, or stomach cancers.

The researchers subsequently demonstrated that they could dial up PD-L1 expression by using CRISPR-Cas9 to interfere with the PD-L1 3'-UTR in mouse or human cell lines, while experiments on mouse models showed diminished immune responses to cancer-causing cells containing such truncations.

Based on such findings, the study's authors speculated that "disrupted PD-L1 3'-UTR might serve as a genetic marker for identifying cancers that actively evade immune surveillance and therefore potentially respond to immune checkpoint blockade using antibodies against PD-1/PD-L1."

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