Listeria monocytogenes-based cancer immunotherapies: Assisting the aging immune system against metastatic cancer

Abstract

Metastatic cancer is responsible for ~90% of all cancer mortality. Immunotherapies can specifically target metastatic cancer cells, however they need to be improved in clinical settings. One factor that often goes ignored in immunotherapy is aging which is essential because immunotherapy is less effective at older age due to T cell unresponsiveness. Lack of naive T cells and increased numbers of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) are both major contributors to tumor-induced immunosuppression and immunosenescence.;My thesis project focused on developing cancer immunotherapies using an attenuated Listeria monocytogenes to overcome T cell unresponsiveness in aging murine tumor models. We demonstrated that Listeria infects MDSCs, which selectively delivers Listeria to the TME. Listeria is able to spread from MDSCs into tumor cells and infected tumor cells become a target for Listeria-activated T cells and NK cells. We hypothesized that Listeria, assisted by MDSC, can generate Listeria-activated NK and T cells against metastases at all ages. Young (3 mo.) and old (18 mo.) BALB/cBy mice were immunized with Listeria, once prior to and twice after 4T1 tumor challenge. We found that Listeria significantly reduced the MDSC population in blood and tumors and induced the production of 1L-12 in a subpopulation of MDSCs, in correlation with strong NK and T cell responses to Listeria. This resulted in a near elimination of metastases and strong regression of tumors in both young and old mice.;Next, we focused on a clinically relevant therapeutic Listeria immunization strategy in the same breast cancer model. Two immunization protocols, weekly high dose (WT) and frequently low dose (FT) therapeutic immunizations, were tested in young and old mice with metastatic breast cancer. We found that the WT immunizations failed to ablate metastatic tumors and to induce immune responses due to immune suppression. However, the FT immunizations were able to induce robust innate and adaptive immune responses, both to Listeria and TAA, which correlated with significant reduction of metastases, in young and old mice. This suggests the potential of Listeria-based immunotherapies to overcome immunosuppression as well as immunosenescence.