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 MYCT9;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.

Brachial FMD and PAT are independent predictors of CV events and all-cause mortality. Further research to evaluate the prognostic utility of PAT is necessary to compare it with FMD as a non-invasive endothelial function test in clinical practice.

Many prospective studies have investigated the relationship between sarcopenic obesity (SO) and risk of mortality. However, the results have been controversial. The aim of the present study was to evaluate the association between SO and all-cause mortality in adults by a meta-analysis of prospective cohort studies. A systematic literature search was carried out through electronic databases up to September 2014. A total of nine articles with 12 prospective cohort studies, including 35 287 participants and 14 306 deaths, were included in the meta-analysis. Overall, compared with healthy subjects, subjects with SO had a significant increased risk of all-cause mortality (pooled HR 1.24, 95% CI 1.12-1.37, P < 0.001), with significant heterogeneity among studies (I(2)  = 53.18%, P = 0.0188), but no indication for publication bias (P = 0.7373). Heterogeneity became low and no longer significant in the subgroup analyses by three SO definitions. More importantly, SO, defined by mid-arm muscle circumference and muscle strength criteria, significantly increased the risk of mortality (HR 1.46, 95% CI 1.23-1.73 and 1.23, 1.09-1.38, respectively). The risk of all-cause mortality did not appreciably change considering the geography (USA cohorts and non-USA cohorts) or the duration of follow up (≥10 years and <10 years). However, the risk estimate was only significant in men (HR 1.23, 95% CI 1.08-1.41, P = 0.0017), not in women (HR 1.16, P = 0.1332). The results of the present study show that subjects with SO are associated with a 24% increase risk of all-cause mortality, compared with those without SO, in particular in men; the significant association was found independent of geographical location and duration of follow up.

Background: Hepatocarcinoma cancer (HCC) occurs more often in men than in women, and little is known about its underlying molecular mechanisms. Results: We identify that 17␤-estradiol (E2) could suppress tumor growth via regulating the polarization of macrophages. Conclusion: Estrogen functions as a suppressor for macrophage alternative activation. Significance: These studies introduce a novel mechanism for suppressing male-predominant HCC.