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Translation control of the immune checkpoint in cancer and its therapeutic targeting.
Xu, Yichen; Poggio, Mauro; Jin, Hyun Yong; Shi, Zhen; Forester, Craig M; Wang, Ying; Stumpf, Craig R; Xue, Lingru; Devericks, Emily; So, Lomon; Nguyen, Hao G; Griselin, Alice; Gordan, John D; Umetsu, Sarah E; Reich, Siegfried H; Worland, Stephen T; Asthana, Saurabh; Barna, Maria; Webster, Kevin R; Cunningham, John T; Ruggero, Davide.
Affiliation
  • Xu Y; Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
  • Poggio M; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • Jin HY; Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
  • Shi Z; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • Forester CM; Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
  • Wang Y; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • Stumpf CR; Department of Developmental Biology, Stanford University, Stanford, CA, USA.
  • Xue L; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Devericks E; Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
  • So L; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • Nguyen HG; Division of Pediatric Allergy, Immunology & Bone Marrow Transplantation, University of California, San Francisco, San Francisco, CA, USA.
  • Griselin A; Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
  • Gordan JD; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • Umetsu SE; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
  • Reich SH; Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
  • Worland ST; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • Asthana S; eFFECTOR Therapeutics, San Diego, CA, USA.
  • Barna M; Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
  • Webster KR; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • Cunningham JT; Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
  • Ruggero D; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Nat Med ; 25(2): 301-311, 2019 02.
Article in En | MEDLINE | ID: mdl-30643286
ABSTRACT
Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5' untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg;KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protein Biosynthesis / Immunotherapy / Liver Neoplasms Type of study: Prognostic_studies Limits: Animals Language: En Journal: Nat Med Journal subject: BIOLOGIA MOLECULAR / MEDICINA Year: 2019 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protein Biosynthesis / Immunotherapy / Liver Neoplasms Type of study: Prognostic_studies Limits: Animals Language: En Journal: Nat Med Journal subject: BIOLOGIA MOLECULAR / MEDICINA Year: 2019 Document type: Article Affiliation country: United States