Structural Variations Disrupting the PD-L1 3′-UTR Enable Immune Evasion

Immunotherapy targeting programmed cell death 1 (PD-1) or its ligand (PD-L1) has been successful in preventing immune escape in many patients with advanced cancer. PD-L1 amplifications or translocations promote immune escape in some tumor types; however, in tumors lacking these alterations, the genetic mechanisms underlying PD-1/PD-L1–mediated immune escape remain unclear. Using whole-genome and RNA sequencing of structural variations (SV) in adult T-cell leukemia/lymphoma, Kataoka, Shiraishi, Takeda, and colleagues identified a prominent recurrent breakpoint cluster within the 3′ region of the PD-L1 locus. Alterations at this locus resulted in elevated expression of abnormal PD-L1 transcripts lacking an intact 3′ untranslated region (UTR), and increased expression of aberrant but functional PD-L1 proteins. Evaluation of tumor samples from The Cancer Genome Atlas revealed clonal selection of cells carrying aberrant 3′-UTR–truncated PD-L1 transcripts in multiple tumor types, including diffuse large B-cell lymphoma and stomach adenocarcinoma. To determine if 3′-UTR loss was responsible for the SV-associated increase in PD-L1 expression, CRISPR/Cas9 was used to introduce large deletions/inversions in the PD-L1 3′-UTR; disruption of the 3′-UTR resulted in elevated PD-L1 expression. Moreover, a tumor cell line expressing both wild-type and 3′-UTR–disrupted PD-L1 exhibited delayed clearance of truncated PD-L1 mRNA compared to wild-type PD-L1, suggesting that the 3′-UTR regulates PD-L1 mRNA stability. Furthermore, loss of the PD-L1 3′-UTR in cancer cells enhanced T-cell apoptosis in co-culture experiments and attenuated antitumor immune responses in vivo. PD-L1 blockade restored cytotoxic T-cell infiltration and tumor regression in mice harboring PD-L1 3′-UTR–disrupted tumors, indicating that PD-L1 overexpression as a result of disruption of the 3′-UTR allowed cells to escape antitumor immunity. Taken together, these findings identify a mechanism by which PD-L1 expression can be enhanced to promote immune escape, and suggest that PD-L1 3′-UTR disruption may be a genetic marker for immune-evading tumors that may respond to PD-1/PD-L1 blockade.

Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S, et al. Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature 2016 May 23 [Epub ahead of print].

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