Mobilizing the low-avidity T cell repertoire to kill tumors.

Optimally, T cells destroy infected and transformed cells of the host. To be effective the T cell repertoire must have a sufficiently diverse number of T cell receptors (TCRs) to recognize the abundance of foreign and tumor antigens presented by MHC molecules. The T cell repertoire must also not be reactive toward self-antigens on healthy cells to prevent autoimmunity. Unlike antigens derived from pathogens, most tumor-associated antigens (TAA) are also self-antigens. Therefore, central and peripheral tolerance mechanisms delete or inhibit tumor-reactive T cells. Although there are T cells within the peripheral repertoire that recognize TAA, these T cells are not sufficient to prevent growth of clinically relevant tumors. We will discuss how this dysfunction results, in part, from the low functional avidity of T cells for tumor, or antigen presenting cells (APC) displaying TAA. We discuss the limitations of these low-avidity tumor-reactive T cells and review current immunotherapies aimed at enhancing the avidity and antitumor activity of the tumor-specific T cell repertoire.