Targeting a self/tumor antigen expressed in the prostate for adoptive T cell immunotherapy of prostate cancer

Adoptive T cell therapy (ACT) for the treatment of established cancers is actively being pursued in clinical trials. However, poor in vivo persistence and maintenance of anti-tumor activity of transferred tumor-specific T cells remain major problems. Most identified tumor antigens are self-proteins, therefore T cells bearing high avidity TCRs for tumor antigens are often deleted in the thymus and any self/tumor-reactive T cells in the periphery are often eliminated or rendered dysfunction by peripheral tolerance mechanisms. The tumor microenvironment poses additional immunosuppressive obstacles, such as the expression of immunosuppressive cytokines and inhibitory ligands. Transforming growth factor beta (TGFbeta) is a potent immunosuppressive cytokine that is required to prevent autoimmunity and is often present at high levels within tumor microenvironments. Programmed death ligand 1 (PD-L1) is an inhibitory ligand that is expressed by many cancers and it's receptor, PD-1, is expressed by many dysfunctional tumor-infiltrating T cells. One advantage of ACT is the ability to genetically engineer T cells to improve function, such as by transducing high affinity tumor-specific TCRs or disrupting inhibitory signaling pathways. In these studies, we used transgenic mouse models to (1) characterize prostate-specific T cell responses to the normal prostate and (2) evaluate the effects of abrogation of TGFbeta and/or PD-1 signaling in self/tumor specific CD8 T cells for use in ACT of prostate cancer.;First, we found that prostate-specific CD8 T cells were subjected to both central and peripheral deletion. Using an adoptive transfer model, we found that in vivo immunization and/or pre-activation of prostate-specific CD8 T cells resulted in prostate infiltration but no subsequent prostate damage. Second, we found that abrogation of TGFbeta signaling increased persistence and augmented anti-tumor activity of self/tumor specific CD8 T cells in a murine model of autochthonous prostate cancer. However, over time, prostate infiltrating T cells became dysfunctional and expressed high levels of PD-1. Moreover, blockade of PD-1 signaling did not rescue or further sustain the function of these cells. These findings reveal that when targeting a tumor antigen that is also expressed as a self-protein, substantive obstacles in addition to TGFbeta and PD-1 are operative within the tumor microenvironment.