IGF::OT::IGF ANTI FUSOBACTERIUM NUCLEATUM VACCINE FOR COLORECTAL CANCER IMMUNOPREVENTION

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Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. While the five-year survival rate for localized CRC is excellent at 90%, more than half of new CRC cases have the disease spread to regional lymph nodes and/or distant organs at the time of diagnosis. CRC with distant metastasis has a dismal five-year survival rate of 13.5%. These data clearly indicate that CRC-related mortality can be significantly improved if the disease is detected early. Risk factors for CRC include age (>50), race (African American), obesity, cigarette smoking, type II diabetes, history of inflammatory bowel diseases, family history of colorectal polyps or CRC, and inherited genetic syndromes known to increase the CRC risks, such as familial adenomatous polyposis (FAP) and Lynch syndrome. FAP and Lynch syndrome are caused by germline mutations in the APC gene and DNA mismatch repair (MMR) genes, respectively. The management of individuals with hereditary gastrointestinal cancer syndromes requires additional measures beyond what is recommended for the average-risk population to minimize the overall risk of cancer-associated morbidity and mortality. Fusobacteria are common human oral gram-negative anaerobic microflora isolated from dental plaque and gum diseases, but rarely detectable in the colorectum of healthy individuals. In recent years, the enrichment of a specific pathotype, Fusobacterium nucleatum (Fn), has been demonstrated in the colonic tissues and stools from patients with colorectal adenomas and CRC. Clinical evidence suggests that the prevalence of Fn progressively increases from dysplasia, adenomas to CRC, and the higher amount of Fn is significantly associated with CRC with high microsatellite instability (MSI-high), which is caused by DNA MMR deficiencies as seen in Lynch syndrome-associated CRC. The potential association of Fn with CRC tumorigenesis has been examined in a mouse model of FAP. ApcMin/+ mice, which carry a nonsense mutation at codon 850 of the Apc gene (Apc∆850), had a significantly accelerated onset and increased multiplicity of both small intestinal and colorectal tumors after oral inoculation of Fn. These data strongly suggested the tumor-promoting role of Fn in ApcMin/+ mice. Although how Fn contributes to CRC tumorigenesis has yet to be fully elucidated, emerging evidence points to its two virulence factors, FadA and Fap2, as potential enhancers of CRC tumorigenesis and progression. FadA adhesin, which is expressed on the bacterial surface, mediates Fn attachment and invasion of endothelial and epithelial cells. A recent study has shown that the Fn FadA binds to E-cadherin and activates Wnt/-catenin signaling, resulting in increased cell proliferation in human colon cancer cells. Disruption of FadA and E-cadherin binding by synthetic inhibitory peptides significantly reduced Fn-driven CRC cell proliferation in vitro and tumor growth in vivo. In the clinical setting, the increased level of FadA expression has been demonstrated in colonic adenoma and CRC tissues obtained from human patients. The Fn Fap2 protein is another virulence factor suggested to play a role in Fn-associated CRC tumorigenesis in humans. The Fap2 binds to human T-cell immunoglobulin ITIM domain (TIGIT), an immunoglobulin superfamily receptor known to function as an immune co-inhibitory molecule. Its ligands, CD155 and CD112, are expressed on antigen presenting cells, T cells as well as on a variety of tumor cells. Fap2-binding to TIGIT on NK and other T cells protects tumor cells from NK cell-mediated cytotoxicity and blocks effector T cell functions in the tumor microenvironment. TIGIT has also been shown to promote Treg function. Taken together, Fn may exert tumor promoting effects not only by promoting CRC tumor growth via activation of Wnt/-catenin signaling pathway, but also by exploiting the immune-suppressive function of TIGIT via the Fap2 protein and contributing to tumor immune evasion mechanisms. Prophylactic vaccines for human papillomavirus (HPV) and hepatitis B virus (HBV) have been associated with significant reductions in infection rates, which are expected to result in the dramatic decrease in the incidence of cervical cancers and hepatocellular carcinoma, respectively. Compared to the prevention of infection, the eradication of oncogenic infectious agents from the host is in general highly challenging, if not impossible. Nontheless, the host immune defense system may be fortified by pathogen-targeted vaccines, if they can boost anti-pathogen immunity and lead to the containment of infection or suppression of pathogen-mediated tumorigenic functions. As with other gram-negative bacteria, Fn produces outer membrane vesicles (OMVs), which contain much of the biological content of the Fn, but without replicative capacity. OMVs are naturally secreted, bi-layered lipid membrane nanostructures of 20-250 nm in size, and are highly stable and immunogenic. OMVs can also be engineered to express specific antigens, while genetically altered to reduce the endotoxicity. As has been demonstrated with the successful development of highly efficacious OMV based anti-meningococcal serogroup B vaccines (i.e. Trumenba® and Bexsero®), Fn OMV may be used as anti-Fn vaccines to elicit immunity that would reduce Fn colonization. The current project will attempt to develop Fn OMV based vaccines (Fn vaccines), which will result in the reduction of Fn colonization in the intestine and colorectum and in turn reduction of the CRC risk in individuals with FAP and Lynch syndrome as well as in other high-risk cohorts.