Lm-LLO-Based Immunotherapies and HPV-Associated Disease

Figure 1

Schematic presentation of LLO-Ag (HPV) fusion protein processing and presentation in antigen-presenting cell (APC) by Listeria monocytogenes. Advaxis in collaboration with Paterson et al. has developed human papilloma virus (HPV) and listeriolysin (LLO) fusion proteins in Lm for immunotherapy [17, 22–24]. Upon injection in vivo, these Lm are sequestered and engulfed by antigen-presenting cells (APCs) such as dendritic cells [23, 24, 31]. The bacteria are engulfed by vacuoles where most of the Listeria are killed [18, 32]. The bacterium while processing the tumor-associated antigen (HPV) and listeriolysin O (LLO) stimulates both arms of the adaptive immune system [20, 34]. Part of the antigen from the vacuole is processed via the MHC class II molecules which generate CD4⁺ T cells. Five to ten percent of these Lm escape into the cytosol with the assistance of the LLO where Listeria can undergo replication. The cytosolic HPV-LLO fusion protein behaves as endogenous antigens. The HPV-LLO fusion protein undergoes ubiquitination, and it is processed via the proteasome [20]. The resulting peptides are presented via the MHC class I molecules to generate CD8⁺ T cells [34]. These cells generate strong cell-mediated immune responses. Lm also evokes a strong innate immune response which leads to generation of numerous mediators such as nitric oxide which is involved in killing of the bacteria in the vacuoles and cytokines (such as TNF-β, IL-1, IL-18, IL-12, and IFNγ) which impart several types of bystander effects [20, 33, 35–37].