E-101 UPR in coordinated regulation of microbiome and anti-tumor immunity

Abstract

RNF5 is a ubiquitin ligase implicated in the control of ER stress and ER associated degradation, part of the greater Unfolded Protein Response. RNF5 mutant mice were found to limit tumor growth, of both melanoma and colon cancer models, owing to enhanced anti-tumor immunity. Enhanced TLR signaling resulted in enhanced infiltration of CD4/8+ T cells as well as Dendritic cells to the tumors grown in RNF5 mutant mice. Cross of RNF5 mutant with MYD88 KO or use of neutralizing antibodies against CD4/8+ T cells effectively attenuated anti-tumor immunity and tumor inhibition phenotypes. Coincided with the enhanced anti-tumor immunity was reduced UPR signaling in intestinal epithelial cells of RNF5 mutant mice. Indeed, cultured intestinal epithelial MODE-K cells that were subjected to inhibition of RNF5 expression exhibited reduced UPR signaling, and were able to activate, in co-culture studies, DC and T cells. Surprisingly, co-housing of RNF5 mutant and WT mice resulted in loss of anti-tumor immunity and the loss of tumor growth inhibition, suggesting that microbiota of RNF5 mutant mice may play a key role in activating anti-tumor immunity. Analysis of gut microbiota composition in RNF5 KO mice led to the identification of specific bacterial strains that were able to induce anti-tumor immunity and limit melanoma growth, when administered to germ free mice. The role of altered UPR in the coordinated regulation of microbiome and anti-tumor immunity will be discussed.