A Novel Dendritic Cell-Based Immunization

The immune system has traditionally been divided into two parts; the innate and the adaptive. The innate immune system’s components include monocytes, macrophages, granulocytes, NK and dendritic cells (DC). The adaptive immune system is composed of antibody-producing B lymphocytes, as well as CD4pos helper T cells and CD8pos cytotoxic T cells. These cells work together to sense, control and eliminate infection. Agents of innate immunity identify microbes through special pattern recognition receptors that sense biochemical structures (usually non-proteins) common to broad classes of potential pathogens

(1). On the other hand, T and B lymphocytes specialize in responding against antigens (usually proteins) specific to the individual species of microbe. DCs have a unique role in that they form a critical bridge between innate and adaptive immunity. Pattern recognition proteins belonging to the Toll-like family of transmembrane receptors (2) induce a maturation and migration program whereby various DC populations, including monocytederived DCs, convey peripherally-acquired proteins to T cells located in the regional draining lymph nodes (3).

The DCs “present” the microbial antigens to T cells in the form of processed peptides complexed with self major histocompatibility proteins (4). This supplies an important signal (signal 1) to T cells that, along with maturation-enhanced co-stimulatory molecule (CD80, CD86) expression (signal 2), can fully activate T cells (5). DCs and some other accessory cells can supply so-called “third signals” (6) that often are expressed in the form of soluble factors, for example, IL-12, IL-23, IL-6 and TGF-beta. Such signals can profoundly influence helper T cell development toward discrete functional phenotypes that include IFN-γ-secreting Th1, IL-17- secreting Th17, as well as anti-inflammatory Treg that produce TGF-beta and IL-10 (7–10).

In many instances, the precise combination of activation signals received by DC dictates whether individual 3rd signal agents will be produced, and hence which Th phenotypes will be selectively induced by the DC (11). Although the immune system evolved primarily to deal with infections, it may be possible to direct it against malignancies. An ideal strategy for inducing anti-tumor immunity must successfully accomplish several goals-some of which are overlapping with traditional antimicrobial vaccines, but others unique to the particular requirements of effective anti-tumor immunity. For example, an effective anti-tumor vaccine must overcome the immune system’s natural tendency to resist the development of strong immunity against self-proteins (i.e. tolerance).

It must also generate immunity of a quality and intensity likely to reduce or eliminate tumor burdens. In the case of therapeutic vaccines, immunity must be effectively induced when disease is already firmly established. Finally, such induced immunity should be durable, so that possible tumor recurrences can be suppressed for long per periods postimmunization.