A unique genetic mechanism underlying a common process that many cancers use to evade the immune system is reported in a paper published online this week in Nature.

The study finds that structural variations to a regulatory sequence in the 3' untranslated region (UTR) of the PD-L1 gene increases expression of the PD-L1 protein, enabling immune evasion by the tumour cells.

The study suggests that the disrupted regulatory sequence may constitute a diagnostic marker to identify patients most likely to benefit from anti-PD-L1 therapy.

"Successful treatment of many patients with advanced cancer using antibodies against PD-1 and its ligand, PD-L1, has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development." the authors, led by Seishi Ogawa, Professor in the Department of Pathology and Tumour Biology, Graduate School of Medicine, Kyoto University, report. "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-tumour immunity through PD-L1 over-expression."

It is known that increased expression of the PD-L1 protein in cancer cells is important in aiding immune escape; if the PD-1 receptor on a T cell binds to PD-L1 on a tumour cell, the T cell becomes unresponsive and does not kill the tumour cell.

Seishi Ogawa and colleagues analysed whole-genome sequences of 49 adult T-cell leukaemia/lymphoma cases for structural variations in the genome, including translocations, inversions, tandem duplications and deletions.

They found that structural variations that disrupt an untranslated regulatory sequence of the PD-L1 gene lead to over-expression of the PD-L1 protein, and that these structural variations are present in 27% of the T-cell leukaemia/lymphoma cases investigated.

The authors looked for these structural variations in over 10,000 different patients across 33 types of cancer.

"The highly recurrent nature of structural variations converging on PD-L1 3′-untranslated region and their common consequence of markedly elevated expression of aberrant but apparently functional PD-L1 proteins in ATL provide strong evidence that SV( ) ATL cells are clonally selected, most likely through escaping immune surveillance. Thus, we hypothesised that a similar mechanism of clonal selection and immune evasion might also operate in other, more prevalent human cancers." says Ogawa.

They found the structural variations are present in many common cancer types, including 8% of diffuse large B-cell lymphomas and 2% of stomach adenocarcinomas. 

They then used the CRISPR/Cas9 genome editing system to disrupt the same untranslated regulatory sequence of the PD-L1 gene in a mouse tumour model, and show that this aids immune escape for the tumour cells.

Addressing the possible impact of this finding, the team says "The surprisingly high efficacy of anti-PD-1/PD-L1 therapy in Hodgkin lymphoma, in which PD-L1 over-expression is frequently associated with genetic defects in PD-L1 , suggests that [PDL-1 antibodies] could be relevant for patients with ATL and other advanced cancers, particularly those for which no effective therapy is currently available"

Source: Nature