Low Affinity TCRs Show Equivalent Antitumor Activity

We have generated, via somatic cell nuclear transfer, two independent lines of transnuclear mice, using as nuclear donors CD8 T cells, sorted by tetramer staining, that recognize the endogenous melanoma antigen tyrosinase related protein 1 (TRP1). These two lines of nominally identical specificity differ greatly in their affinity for antigen (TRP1high or TRP1low) as inferred from tetramer dissociation and peptide responsiveness. Ex vivo–activated CD8 T cells from either TRP1high or TRP1low mice show cytolytic activity in three-dimensional tissue culture and in vivo, and slow the progression of subcutaneous B16 melanoma. Although na€ve TRP1low CD8 T cells do not affect tumor growth, upon activation these cells function indistinguishably from TRP1high cells in vivo, limiting tumor cell growth and increasing mouse survival. The antitumor effect of both TRP1high and TRP1low CD8 T cells is enhanced in RAG-deficient hosts. However, tumor outgrowth eventually occurs, likely due to T cell exhaustion. The TRP1 transnuclear mice are an excellent model for examining the functional attributes of T cells conferred by T cell receptor (TCR) affinity, and they may serve as a platform for screening immunomodulatory cancer therapies. Cancer Immunol Res; 1(2); 99–111. 2013 AACR