2. Academic Validation
  3. Translation control of the immune checkpoint in cancer and its therapeutic targeting

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

  • Nat Med. 2019 Feb;25(2):301-311. doi: 10.1038/s41591-018-0321-2.
Yichen Xu 1 2,  Mauro Poggio 1 2,  Hyun Yong Jin 1 2,  Zhen Shi 3 4,  Craig M Forester 1 2 5,  Ying Wang 1 2 6,  Craig R Stumpf 1 2 7,  Lingru Xue 1 2,  Emily Devericks 1 2,  Lomon So 1 2,  Hao G Nguyen 1 2,  Alice Griselin 1 2,  John D Gordan 2,  Sarah E Umetsu 8,  Siegfried H Reich 7,  Stephen T Worland 7,  Saurabh Asthana 2,  Maria Barna 3 4,  Kevin R Webster 7,  John T Cunningham 1 2 9,  Davide Ruggero 10 11 12
Affiliations

Affiliations

  • 1 Department of Urology, University of California, San Francisco, San Francisco, CA, USA.
  • 2 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • 3 Department of Developmental Biology, Stanford University, Stanford, CA, USA.
  • 4 Department of Genetics, Stanford University, Stanford, CA, USA.
  • 5 Division of Pediatric Allergy, Immunology & Bone Marrow Transplantation, University of California, San Francisco, San Francisco, CA, USA.
  • 6 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
  • 7 eFFECTOR Therapeutics, San Diego, CA, USA.
  • 8 Department of Pathology, University of California, San Francisco, CA, USA.
  • 9 Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 10 Department of Urology, University of California, San Francisco, San Francisco, CA, USA. davide.ruggero@ucsf.edu.
  • 11 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. davide.ruggero@ucsf.edu.
  • 12 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. davide.ruggero@ucsf.edu.
PMID: 30643286 DOI: 10.1038/s41591-018-0321-2
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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