Targeting Tim-1 to Circumvent Immune Tolerance in Prostate Cancer

We have previously shown that manipulating lymphocytes through Tim1 receptor, a membrane protein that regulates the vigor and differentiation of T cells, using an agonist monoclonal antibody, enhances cytotoxic lymphocyte (CTL) responses to a model prostate tumor-associated antigen (SV40 T antigen) in tumor-free and tumor-bearing mice. This provided a tool to break immune tolerance to prostate tumor antigens in prostate cancer. We now demonstrate, using Tim1 deficient mice, that the effect of the antibody is mediated through Tim-1. We additionally demonstrate that its effect is maintained in humanized HLAA2.1 transgenic mice when these mice are immunized with peptides derived from the prostate tumor antigens ERG and SIM2. A similar effect was obtained in HLA-A2.1/ERG and HLA-A2.1/ERG/TRAMP. Our findings provide evidence that manipulating Tim1 with an agonist antibody at time of vaccination strengthens cytotoxic responses to mouse and human prostate tumorassociated antigens in healthy and prostate tumor-bearing mice. This represents a major step towards preclinical testing of this strategy against prostate tumor growth and progression and its translation into therapy for prostate cancer in humans.
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