Dendritic cells in immunotherapy of established cancer: Roles of signals 1, 2, 3 and 4.

Despite the ability of cancer vaccines to induce tumor-specific T-cells in the blood of patients with cancer, and early, promising data indicating their ability to delay cancer progression, their ability to induce cancer regression remains low. The use of ex vivo-generated dendritic cells (DCs) in such vaccines can help to sidestep the cancer-associated dysfunction of endogenous DCs and to deliver the key instructive signals needed for effective antitumor responses. Effective ways of loading DCs with tumor-related antigens, while retaining the high costimulatory function required for T-cell expansion (ie, effective delivery of 'signal one' and 'signal two'), have been previously identified. More recently, different DC populations have been found to deliver a specialized third signal, able to regulate the acquisition of desirable T-cell effector functions, as well as an additional fourth signal that regulates the homing properties of T-cells. Moreover, ex vivo instruction of DCs can be used to preferentially activate CTLs, T-helper 1 and NK cells, while limiting the undesirable activation of regulatory T-cells. These developments can result in the induction of T-cells with desirable effector functions and tumor-relevant homing properties, even in the absence of proinflammatory signals (typically present in recall infections, but not in advanced cancer), thus helping to bridge the gap between the effectiveness of therapeutic and preventive cancer vaccines.