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
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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

Abstract:

      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.

References:

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