Virally-induced tumorigenesis controlled by the microbiota

Abstract All multicellular organisms are colonized with a diverse and complex population of microbes including bacteria, viruses, fungi, archaea, and protozoans, collectively called the microbiota. Microbiota play an integral role in modulating host health by providing necessary nutrients, by protecting against incoming bacterial pathogens and by supporting the development and maturation of the immune system. Microbiota could also impact cancer development at various stages by modulating cell proliferation and death, altering the function of the immune system, and influencing metabolism of various compounds. Murine Leukemia Virus (MuLV) is highly proficient in causing leukemia in mice from susceptible strains. Using MuLV, we found that some gut commensal bacteria promoted the development of leukemia induced by this retrovirus. The promotion of leukemia development by commensal bacteria was due to suppression of the adaptive immune response through upregulation of several negative regulators of immunity. These negative regulators included serine (or cysteine) peptidase inhibitor, clade B, member 9b (Serpinb9b) and Ring finger protein 128 (Rnf128). Serpinb9b is known to counteract killing by cytotoxic granzymes and was upregulated in leukemic cells. Rnf128 known for induction of unresponsiveness of T cells was induced uniquely in CD4 T cells. Genetic ablation of these genes conferred resistance to virally-induced leukemia even in the presence of a complex microbiota. Upregulation of Serpinb9b was mediated via the RIPK2 pathway (downstream of NOD1 and NOD2 receptors which detect various forms of peptidoglycan). As Serpinb9b and Rnf128 are associated with a poor prognosis of some spontaneous human cancers, the mechanism of bacterially-induced immunosuppression during tumor development may apply to human tumors of virally and non-viral origin. The current proposal aims at defining the precise mechanism(s) by which microbially-induced negative immune regulators contribute to leukemia progression. Specifically, we will identify the innate immune receptors bacterial products signal through to induce negative immune regulators and determine the adoptive mechanism which controls leukemia development in the absence of bacteria.