Project 458678

Recently, two bacteria that colonize the human intestinal tract, Fusobacterium nucleatum (Fn) and enterotoxigenic Bacteroides fragilis (ETBF), have been found to be related to the development of colorectal cancer (CRC). Fn is able to invade into colon cells and ETBF secretes a toxin called BFT, which can also enter cells. The entry of these bacteria or toxins into our cells causes various alterations that can lead to cancer. However, our immune system is typically able to combat such bacterial infiltrations through antigen presentation. Proteins within cells are constantly being broken down into fragments called antigens. Antigens can then bind to a protein called MHC, and MHC shuttles these antigens to the host cell surface for presentation to immune cells. CD8+ T cells are specialized immune cells that inspect presented antigens on other cells and discriminate normal "self" antigens from "non-self" antigens, such as bacterial antigens. Once a "non-self" antigen is recognized, CD8+ T cells activate and kill the infected cell. Cells compromised by Fn invasion or BFT toxin entry, and therefore at risk to become cancerous, possess bacterial antigens that CD8+ T cells should respond to. However, it is currently unknown why cells with Fn or BFT are not sufficiently killed by CD8+ T cells in CRC, and whether generating a CD8+ T cell response to these bacteria may be protective or therapeutic. To address this knowledge gap, we have identified antigens from Fn and BFT that are presented and induce strong CD8+ T cell responses in healthy individuals. Next, we will characterize if these responses lead to elimination of infected host cells and assess potential differences in CRC patient responses. Lastly, we will test our candidate antigens in mRNA vaccine designs and evaluate whether these responses are protective from CRC. This work will provide foundational data towards the goal of developing effective CD8+ T cell-activating vaccines that protect from colorectal cancer.