gene'cs 8 Blood 6 Nat Commun 2 他多数 京都大学小川誠司研究室における成果 LETTER doi:10.1038/nature18294 Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers Keisuke Kataoka1*, Yuichi Shiraishi2*, Yohei Takeda3*, Seiji Sakata4, Misako Matsumoto3, Seiji Nagano5, Takuya Maeda5, Yasunobu Nagata1, Akira Kitanaka6, Seiya Mizuno7, Hiroko Tanaka2, Kenichi Chiba2, Satoshi Ito2, Yosaku Watatani1, Nobuyuki Kakiuchi1, Hiromichi Suzuki1, Tetsuichi Yoshizato1, Kenichi Yoshida1, Masashi Sanada8, Hidehiro Itonaga9, Yoshitaka Imaizumi10, Yasushi Totoki11, Wataru Munakata12, Hiromi Nakamura11, Natsuko Hama11, Kotaro Shide6, Yoko Kubuki6, Tomonori Hidaka6, Takuro Kameda6, Kyoko Masuda5, Nagahiro Minato13, Koichi Kashiwase14, Koji Izutsu15, Akifumi Takaori-Kondo16, Yasushi Miyazaki10, Satoru Takahashi7, Tatsuhiro Shibata11,17, Hiroshi Kawamoto5, Yoshiki Akatsuka18,19, Kazuya Shimoda6, Kengo Takeuchi4, Tsukasa Seya3, Satoru Miyano2 & Seishi Ogawa1 Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development1–6. However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma6–10. Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3′ region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3′-untranslated region (UTR). Disruption of the Pd-l1 3′-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. 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 applied to a set of WGS data from 49 cases of adult T-cell leukaemia/ lymphoma (ATL), a retrovirus-associated aggressive peripheral T-cell neoplasm15. RNA sequencing (RNA-seq) data were also available for 43 samples (Extended Data Fig. 1a and Supplementary Table 1). Genome-wide mapping of SV-associated breakpoints revealed a number of recurrent breakpoint cluster regions. Among these, the most prominent corresponded to breakpoints at chromosome 9p24.1 found in 13 (26.5%) samples, which were narrowly clustered in a 3.1 kilobase (kb) region within the 3′ region of the PD-L1 locus (Extended Data Fig. 1b and Supplementary Table 2). Depending on samples, a variety of SV types were observed, including a large deletion (n = 1), tandem duplications (n = 4), inversions (n = 4), and translocations (n = 4) (Fig. 1a and Extended Data Fig. 1c). However, irrespective of under- lying SV types, an aberrant PD-L1 allele was generated in all cases, where the authentic 3′ exons were replaced by an ectopic sequence derived from the rearranged loci (n = 12) or a short 327 base pair (bp) sequence within the last exon was inverted (ATL017). It was appar- ent that these SVs were invariably associated with markedly elevated expression of PD-L1, except for a single case (ATL068) with very low tumour content (Fig. 1b). As expected from the underlying SV structure, all overexpressed PD-L1 transcripts underwent structural alterations, which, on the basis of RNA-seq, fused varying lengths of the 5′ region of the PD-L1 sequence to a short tract of intronic or
friend1ws
kentaitakura
mansuy
utig
tereka114
roadroller
.jpg){kind=avatar}
ktatsuya
.jpg){kind=avatar}
kojinishiguchi
melix
hachama
aronwalsh
techmathproject
hayataka88
rocio
thoeni
kastner
3n
scottboms
cassininazir
keavy
holman
chrislema
jponch
garrettdimon
mongodb
