Translation control of the immune checkpoint in cancer and its therapeutic targeting
| Autor: | Saurabh Asthana, Mauro Poggio, Reich Siegfried Heinz, Hyun Yong Jin, Sarah E. Umetsu, Zhen Shi, Lomon So, Craig R. Stumpf, Hao G. Nguyen, Alice Griselin, Craig M. Forester, John D. Gordan, Stephen T. Worland, Kevin R. Webster, John T. Cunningham, Emily Devericks, Maria Barna, Ying Wang, Lingru Xue, Davide Ruggero, Yichen Xu |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Transcription Genetic Pyridines medicine.medical_treatment Down-Regulation Kaplan-Meier Estimate Biology General Biochemistry Genetics and Molecular Biology Article B7-H1 Antigen Proto-Oncogene Proteins c-myc Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Open Reading Frames 0302 clinical medicine medicine Tumor Microenvironment Animals Neoplasm Metastasis Immune Evasion Tumor microenvironment Oncogene Base Sequence EIF4E Liver Neoplasms Cancer General Medicine Immunotherapy medicine.disease Immune checkpoint Up-Regulation Immunosurveillance Gene Expression Regulation Neoplastic Mice Inbred C57BL 030104 developmental biology Eukaryotic Initiation Factor-4E Pyrimidines 030220 oncology & carcinogenesis Protein Biosynthesis Cancer cell Cancer research Disease Progression 5' Untranslated Regions |
| Popis: | 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 (MYC(Tg)) synergizes with KRAS(G12D) to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRAS(G12D) alone. Genome-wide ribosomal footprinting of MYC(Tg);KRAS(G12) tumors compared with KRAS(G12D) revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRAS(G12D) tumors by functional, non-canonical upstream open reading frames in its 5′ untranslated region, which is bypassed in MYC(Tg);KRAS(G12D) 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 MYC(T9);KRAS(G12D) 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. |
| Databáze: | OpenAIRE |
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