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Merck

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

Nature medicine (2019-01-16)
Yichen Xu, Mauro Poggio, Hyun Yong Jin, Zhen Shi, Craig M Forester, Ying Wang, Craig R Stumpf, Lingru Xue, Emily Devericks, Lomon So, Hao G Nguyen, Alice Griselin, John D Gordan, Sarah E Umetsu, Siegfried H Reich, Stephen T Worland, Saurabh Asthana, Maria Barna, Kevin R Webster, John T Cunningham, Davide Ruggero
ANOTACE

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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