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.
McMahan
Rachel H
RH
Integrated Department of Immunology, University of Colorado at Denver and Health Sciences Center, Denver, CO 80206, USA.
Slansky
Jill E
JE
D000818:Animals; D015551:Autoimmunity; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte