Translation control of the immune checkpoint in cancer and its therapeutic targeting (Nature Medicine2019, 25:301-311.)

報告日期: 2019/10/25
報告時間: 15:10/16:00
報告學生: 黃思璇
講評老師: 余建泓

Translation control of the immune checkpoint in cancer and its therapeutic targeting

Nature Medicine volume 25, 301–311 (2019)

Yichen Xu, Mauro Poggio, John T. Cunningham. Davide Ruggero et al.

Speaker: Si-Xuan Huang (黃思璇)                           Time: 2019/10/25 3:10-4:00 pm

Commentator: Chien-Hung Yu Ph.D. (余建泓老師)   Place:  醫學院 602


      The immune-checkpoint pathways are play an important role in control of tumor metastasis. However, tumor cells can evade detection by the immune response. In previous studies, the transcriptional control of immune-checkpoint inhibitor by specific oncogenic control was found, whereas the post-transcriptional control still remains uncharacterized. To understand how the post-transcriptional control affects immune-checkpoint pathways in tumor cell. The authors focused on hepatocellular carcinoma (HCC). They established two mouse models, one was MYC and KRAS (MYCTg;KRASG12D) which could induced HCC and aggressive tumor, another one was KRAS(KRASG12D) alone which compared with MYCTg;KRASG12D. The authors analyzed the global transcriptome and translatome profiles, these performed the gene ontology analysis in MYCTg;KRASG12D versus KRASG12D alone and KRASG12D alone versus wild-type. In translatome profiles result, PD-L1 which could downregulate T cell activation by interact with PD-1 was upregulated in MYCTg;KRASG12D, but not in transcriptome profiles. It indicated that PD-L1 was upregulated in translation of the gene. In Toeprint assay, the authors found that PD-L1 translation through bypassing non-canonical upstream open reading frame (uORFs) in KRASG12D alone. Then the authors injected two individual uORFs mutant KRASG12D clones to stimulate PD-L1 translation. The results showed that the activity of PD-L1 was a key factor of cancer aggressiveness. The author also used eFT508, a clinical translation inhibitor, could down regulate PD-L1 and prevent liver tumor progression and metastasis. These findings strongly indicate how immune-checkpoint control by MYC and KRAS at mRNA translation.


  1. Casey, S. C. et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352, 227–231 (2016).