Gut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5−/− mice

Abstract

Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells. Reduced UPR expression is also seen in murine and human melanoma tumor specimens that responded to immune checkpoint therapy. Co-housing of Rnf5 −/− and WT mice abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium , enriched in Rnf5 −/− mice, establishes anti-tumor immunity and restricts melanoma growth in germ-free WT mice. Altered UPR signaling, exemplified in Rnf5 −/− mice, coincides with altered gut microbiota composition and anti-tumor immunity to control melanoma growth.

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…As our understanding of the gut microbiome grows, we have recently come to appreciate intriguing evidence suggesting that the gut microbiome plays a momentous role in tumorigenesis and progression, especially extraintestinal neoplasms, such as hepatocellular carcinoma, 32 mammary cancer, 33 pancreatic cancer, 344 and melanoma. 35 We seek to summarize the latest data demonstrating alterations in the intestinal microbiota of patients with the abovementioned extraintestinal cancers ( Table 2).…”

“…For example, a consortium of 11 bacterial strains, including B. rodentium, establishes anti-tumor immunity and confines melanoma growth when inoculated into GF mice. 35 There are discrepancies in the intestinal microbial composition and metabolic functions between patients with and without prostate cancer; [437][438][439][440] for instance, the aberrant metabolome of individuals with prostate cancer is characterized by the presence of high levels of bacteria associated with carbohydrate metabolism pathways while lacking bacteria associated with folate production. 437 Compared with male patients with prostate cancer, men without prostate cancer are characterized by higher αdiversity in the gut microbiome.…”

“…23 It can also impact extraintestinal organs in distant parts of the body through diversiform and distinct mechanisms, including the translocation of the gut microbiome or/and their structure and components, the circulation of microbial-derived metabolites or endocrine molecules, the migration of immune cells and factors, and the modulation of gut-brain axis signaling through the vagal nerve, leading to neuropsychiatric diseases (depression, autism), 16,24 autoimmune diseases (autoimmune diabetes, systemic lupus erythematosus, and allergies), [25][26][27] metabolic diseases (obesity, type 2 diabetes, nonalcoholic fatty liver), [28][29][30][31] and even extraintestinal tumors (hepatocellular carcinoma, breast cancer, pancreatic cancer, and melanoma). [32][33][34][35] Notably, there is a wide array of evidence that microbial metabolites derived from ingested nutrients (such as short-chain fatty acids (SCFAs), microbial tryptophan (TRP) catabolites, and succinate) are pivotal inducers of such effects.…”

Composition of the murine gut microbiome impacts humoral immunity induced by rabies vaccines

“…Recently, germ-free (GF) mice are introduced to explore the function of the gut microbiome in adaptive immune responses. 4,41,42 GF mice have a small number of intraepithelial lymphocytes and have difficulty in balancing helper T-cell subsets, resulting in a depressed immune response. Although GF mice are an optimal model for studying the relationship between immunity and the gut microbiome, they need strictly sterile feeding environment and high breeding expenses.…”

Melanoma to Vitiligo: The Melanocyte in Biology & Medicine–Joint Montagna Symposium on the Biology of Skin/PanAmerican Society for Pigment Cell Research Annual Meeting

“…Mice lacking RNF5 were more resistant to developing melanoma, dependent on their gut microbiome. Bacterial strains were mapped and shown to be capable of eliciting antitumor immunity and inhibiting tumor growth, involving altered unfolded protein response in intestinal epithelial cells and affecting antigen presentation and antimicrobial peptide expression (Li et al, 2019).…”