The Problem: Tumor Immunity Is Not Effectively Induced in Tumor-bearing Hosts. Animal experiments as well as clinical experience, notably in melanoma, indicate that the immune system can recognize and kill tumor cells. In particular, CTLs recognize MHC class I–peptide complexes on the tumor cell surface, and the peptides are derived from nonmutated or mutated genes that can be primarily expressed in the tumors (1–3). Why then does the immune system fail to eradicate most antigenic cancers? One clue is the observation that CTLs for melanoma and other human tumors are not known to be expanded. For example, CTL precursors are not increased in melanoma patients, whereas humans who are infected with a virus like influenza frequently show expansions in virus-specific CTLp. Therefore tumors have antigens for T cells, but these do not appear to be immunogenic in vivo.

The Hypothesis: Lack of Tumor Antigen Presentation by Dendritic Cells In Vivo Is a Major Problem that Can Be Bypassed by Delivery of Tumor Antigens on Autologous Dendritic Cells. One possible reason for a lack of tumor immunity is that the antigens are not being presented by dendritic cells (DCs). DCs are antigen-presenting cells that are specialized to prime helper and killer T cells in vivo (recently reviewed in references 4 and 5). To do so, DCs perform a series of coordinated tasks. Immature DCs develop from hematopoietic progenitors and are strategically located at body surfaces and in interstitial spaces of most tissues. There, DCs are equipped to capture antigens and to produce large numbers of immunogenic MHC–peptide complexes. In the presence of maturation-inducing stimuli such as inflammatory cytokines or stimulation via CD40 (6), DCs upregulate adhesion and costimulatory molecules to become more potent, terminally differentiated, stimulators of T cell immunity. At the same time, numerous intracellular MHC II compartments seem to discharge MHC II–peptide complexes to the cell surface where they can be unusually long lived (7, 8). DCs also migrate to secondary lymphoid organs to select and stimulate rare antigen-specific T cells (9, 10). Nonetheless, there is no evidence that DCs capture and process antigens from malignant cells in vivo. Tumors, for example, can make products like IL-10 (11, 12) and vascular endothelial growth factor (13) that could decrease DCs development and function. Is a lack of tumor antigen presentation by DCs a major problem in generating T cell–mediated resistance to tumors in vivo? If so, could DCs be used as adjuvants to induce strong tumor-specific immunity?