Overcoming dendritic cell-mediated suppression of T cell responses in a prostate tumor environment

Abstract

Prostate cancer is the most prevalent malignancy in American men, leading to significant mortality each year. This is in part due to a lack of effective treatments for advanced disease. The prostate is considered an ideal organ for cancer immunotherapy, because it is both nonessential and expresses several prostate-specific antigens than could be targeted for an immuno- therapeutic response. However, such therapy is limited by the tolerization of CD8⁺ T cells in tumors, rapidly abrogating anti-tumor responses. In order to better understand the factors necessary to induce, maintain and promote productive T cell responses against cancer, this research has focused on understanding and interrupting critical interactions between CD8⁺ T cells and immunosuppressive networks within tumors. As our model system, we explored CD8⁺ T cell recognition of spontaneous prostate cancer in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. We demonstrated that both naive and effector tumor-reactive T cells are rapidly tolerized in the prostates and prostate draining lymph nodes (PDLN) of TRAMP mice, and that dendritic cells are important factors driving their tolerization. We then developed two novel immuno- therapeutic approaches to locally overcome the suppressive influence of dendritic cells. In one approach, we engineered tumor-reactive T cells to express the immunostimulatory protein CD40 ligand to mature dendritic cells in the PDLN. This work demonstrated for the first time that tumor-reactive T cells could be engineered to deliver stimulatory signals to dendritic cells in tumor environments to enhance the function of adoptively transferred T cells. In a second approach, we injected ex vivo matured, antigen-loaded dendritic cells into tumors to overcome the influence of endogenous suppressive dendritic cells. This work demonstrated for the first time that intratumoral injections of dendritic cells into spontaneous primary tumors could significantly delay the tolerization of tumor-infiltrating effector T cells and reverse the tolerization of resident tumor-infiltrating lymphocytes (TILs), generating new potential therapeutic applications for TILs. These two approaches establish that mechanism-based immuno- therapeutic interventions can be rationally designed to locally interrupt immunosuppressive networks within tumors. As the TILs enhanced through this work are representative of those found in cancer patients, such approaches could have significant clinical impact.