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TY - JOUR AU - Pardoll, Drew M. PY - 2002 DA - 2002/04/01 TI - Spinning molecular immunology into successful immunotherapy JO - Nature Reviews Immunology SP - 227 EP - 238 VL - 2 IS - 4 AB - Tumour antigens that are potential targets for therapeutic immune responses are being identified. They can be divided into four categories: unique tumour-specific antigens that are the products of mutation; viral antigens in virus-associated cancers; tissue-specific differentiation antigens; and tumour-selective antigens. As dendritic cells (DCs) are the crucial antigen-presenting cells that activate T-cell-dependent immune responses, enhancing their function is a central goal of new therapeutic vaccine strategies. The most common approach involves arming vaccines with genes that encode molecular signals for DC mitogenesis and/or activation. Another important strategy for enhancing immunotherapy involves approaches to target antigen more effectively to DCs. Antigens can be targeted either extracellularly (by linking them to ligands that bind to DC surface receptors) or intracellularly (by linking them to intracellular sorting signals that target MHC processing pathways). The modification of antigenic residues can enhance the potency of antigen-specific vaccines, through amino-acid substitutions that enhance the affinity of the antigen for either MHC or T-cell receptor. Therapeutic vaccines can be enhanced by the incorporation of genes that encode co-stimulatory molecules. The growing list of both B7 and tumour-necrosis factor family co-stimulatory molecules offers a tremendous range of opportunities in vaccine design. It is now clear that the quantitative response to antigen is the result of a balance between both positive (co-stimulatory) and negative (checkpoint) signalling pathways. Immunotherapies can be enhanced markedly through the blockade of negative regulatory pathways (so-called immunological checkpoints). For all of the added value that recombinant DNA technology provides in engineering elements into vaccine constructs that enhance their potency, nature itself provides a virtually limitless array of delivery systems, in the form of diverse microbes with potent intrinsic immunological properties. Viruses, bacteria and fungi have all been engineered as vectors for therapeutic vaccination. SN - 1474-1741 UR - https://doi.org/10.1038/nri774 DO - 10.1038/nri774 ID - Pardoll2002 ER -