Uveal melanoma (UM) is the most common primary cancer of the eye in adults and progresses to metastatic disease predominantly of the liver in ∼50% of patients. In these cases, life expectancy averages just 9 months due to the lack of effective treatment options. The Toll-like receptor 5 (TLR5) agonist entolimod (former name CBLB502) rapidly activates TLR5-NF-κB signaling in hepatocytes and suppresses growth of both TLR5-expressing and non-expressing tumors in the liver through mobilization and activation of innate and adaptive immune mechanisms. The goal of this study was to explore the potential of entolimod as an immunotherapeutic agent against hepatic metastasis of UM using the TLR5-positive B16LS9 mouse model of ocular melanoma. Mice were given seven subcutaneous injections of vehicle or entolimod given 72 h apart started one day before, on the same day or three days after intraocular injection of B16LS9 cells. All tested regimens of entolimod treatment resulted in significantly reduced B16LS9 metastasis to the liver. Entolimod induced mobilization of natural killer (NK) cells to the liver and stimulated their maturation, differentiation and activation. Antibody-mediated depletion of NK cells from mice abrogated entolimod's antimetastatic activity in the liver and eliminated the entolimod-elicited in vitro cytotoxic activity of hepatic lymphocytes against B16LS9 cells. These results provide pre-clinical evidence of entolimod's efficacy against hepatometastasis of UM and support its further development as an anticancer immunotherapeutic drug.

The receptor-interacting protein kinase 1 (RIPK1) is an essential signaling molecule in pathways for cell survival, apoptosis, and necroptosis. We report here that RIPK1 is upregulated in human colorectal cancer and promotes cell proliferation when overexpressed in a colon cancer cell line. RIPK1 interacts with mitochondrial Ca 2þ uniporter (MCU) to promote proliferation by increasing mitochondrial Ca 2þ uptake and energy metabolism. The ubiquitination site of RIPK1 (RIPK1-K377) was critical for this interaction with MCU and function in promoting cell proliferation. These findings identify the RIPK1-MCU pathway as a promising target to treat colorectal cancer.Significance: RIPK1-mediated cell proliferation through MCU is a central mechanism underlying colorectal cancer progression and may prove to be an important therapeutic target for colorectal cancer treatment. Cancer Res; 78(11); 2876-85. Ó2018 AACR.

No abstract

Edited by Tamas Dalmay Keywords:Highly pathogenic H5N1 avian influenza Chicken Duck MicroRNA Immune organ a b s t r a c tChickens are susceptible to the highly pathogenic H5N1 strain of avian influenza virus (HPAIV), whereas ducks are not. Here, we used high-throughput sequencing to analyse the microRNA expression in the spleen, thymus and bursa of Fabricius of H5N1-HPAIV-infected and non-infected chickens and ducks. We annotated the genomic positions of duck microRNAs and we compared the microRNA repertoires of chickens and ducks. Our results showed that the microRNA expression patterns in the homologous immune organs of specific-pathogen-free (SPF) chickens and ducks diverge substantially. Moreover, there was larger divergence between the microRNA expression patterns in immune organs of HPAIV-infected chickens than HPAIV-infected ducks. Together, our results might help to elucidate the roles of microRNAs in the divergent immunity of chickens and ducks against H5N1 HPAIV.

No abstract