Breaking immune tolerance to prostate-associated tumor antigens through Tim-1 receptor (162.20)

Abstract

Abstract It has been suggested that one factor limiting cancer immunotherapy in clinical trials are immunological checkpoints that impede vaccine-induced anti-tumor responses. We postulate that manipulating lymphocytes and dendritic cells through the Tim-1 receptor, a membrane protein that regulates the vigor and differentiation of these cells, using an agonist monoclonal antibody could enhance cytotoxic lymphocyte (CTL) responses to prostate tumor-associated antigens. We used an approach that combines concomitant immunization against a model prostate tumor-associated antigen (TAA) SV40 Tag and treatment with an agonist anti-Tim1 antibody and assessed Tag-specific CTL responses two weeks later. Ab treatment of TRAMP mice resulted in elevated Tag-specific CTL in both spleen and prostate-draining lymph nodes, indicating that manipulating Tim1 results in circumventing immune tolerance to Tag antigen. We then tested this strategy for human epitopes derived from the prostate cancer-specific antigen ERG and SIM2 by combining anti-Tim1 antibody with an ERG- and SIM2-derived HLA-A2.1-restricted peptide vaccine in HLA-A2.1 transgenic mice and showed that CTL responses to ERG and SIM2 epitopes are elevated in the presence of anti-Tim1 Ab. Further characterization of lymphocyte differentiation post-immunization/anti-Tim1 treatment revealed that major shifts in T cell differentiation occur. Our findings suggest that targeting Tim1 could be successfully combined with prostate cancer vaccines.